Novel solid materials of  and methods for obtaining them

ABSTRACT

The instant invention relates to novel solid materials of {[(2S,5R,8S,11S)-5-Benzyl-11-(3-guanidino-propyl)-8-isopropyl-7-methyl-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid}, methods for producing them, and the use of said solid materials in pharmaceuticals.

The instant invention relates to novel solid materials of{[(2S,5R,8S,11S)-5-Benzyl-11-(3-guanidino-propyl)-8-isopropyl-7-methyl-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-aceticacid}, methods for producing them, and the use of said solid materialsin pharmaceuticals.

{[(2S,5R,8S,11S)-5-Benzyl-11-(3-guanidino-propyl)-8-isopropyl-7-methyl-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-aceticacid} or cyclo-(Arg-Gly-Asp-DPhe-NMe-Val) was first described in thepatents/patent applications U.S. Pat. No. 6,001,961 and EP 0 770 622,which were first published in 1997. In said patents, various salt formsof said compound were described, e.g. the hydrochloride, the acetate andthe methansulfonate. Later, an improved method of manufacture that ledto the inner salt of cyclo-(Arg-Gly-Asp-DPhe-NMe-Val) was described inWO 00/53627. However, the solids obtained according to the describedprocedures appeared to be amorphous material.

Pharmaceutical activity is of course the basic prerequisite to befulfilled by a pharmaceutically active agent, pharmaceutically activeprinciple or active pharmaceutical ingredient (API) before same isapproved as a medicament on the market. However, there are a variety ofadditional requirements a pharmaceutically active agent has to complywith. These requirements are based on various parameters which areconnected with the nature of the active substance itself. Without beingrestrictive, examples of these parameters are the stability of theactive agent or active ingredient under various environmentalconditions, its stability during production of the pharmaceuticalformulation and the stability of the active agent or active ingredientin the final medicament compositions. The pharmaceutically activesubstance used for preparing the pharmaceutical compositions should beas pure as possible and its stability in long-term storage must beguaranteed under various environmental conditions. This is absolutelyessential to prevent the use of pharmaceutical compositions whichcontain, in addition to the actual active substance, breakdown ordecomposition products thereof, for example. In such cases the contentof active substance in the medicament might be less than that specifiedand/or the medicament might fail quality control.

Technical factors like the particle size or uniform distribution of theactive principle or active ingredient in the formulation can be criticalfactor, particularly when the medicament is a complex formulation and/orthe medicament has to be given in low doses. To enable complexformulation systems and/or to ensure uniform distribution, the particlesize of the active substance can be adjusted to a suitable level, e.g.by grinding. Since breakdown of the pharmaceutically active substance asa side effect of processing steps, such as purification, dissolution,melting, grinding, micronising, mixing and/or extruding has to beminimized, despite the harsh conditions required during said processingsteps, it is absolutely essential that the active substance is highlystable throughout said processing steps. Only if the active substance issufficiently stable during the processing steps, it is possible toproduce a homogeneous pharmaceutical formulation which always fulfilsthe quality requirements and contains the specified amount of activesubstance in reproducible manner.

Another problem which may arise in the grinding process for preparingthe desired pharmaceutical formulation is the input of energy and/orpressure caused by the process steps, such as the stress on the surfaceof the particles of the API, no matter whether it is amorphous orcrystalline. This may in certain circumstances lead to polymorphicchanges, to a change in the amorphous configuration or to a change inthe crystal lattice, depending on the solid material or form employed inthe processing steps. Since the pharmaceutical quality of apharmaceutical formulation requires that the active substance shouldalways have the same morphology, preferably the same crystallinemorphology, the stability and properties of the solid API are subject tostringent requirements from this point of view as well. Thus, thestability and also a long shelf life of the API itself is of realimportance.

Many pharmaceutical solids can exist in different physical forms.Polymorphism is preferably characterized as the ability of a compound,such as a drug substance, to exist in two or more crystallinemodifications that have different arrangements and/or conformations ofthe molecules in the crystal lattice (D. J. W. Grant. Theory and originof polymorphism. In H. G. Brittain (ed.) Polymorphism in PharmaceuticalSolids. Marcel Dekker, Inc., New York, 1999, pp. 1-34, the disclosure ofwhich is incorporated into this application by reference in itsentirety). Amorphous solids consist of disordered arrangements ofmolecules and do not possess a crystal lattice and/or a long rangeorder. Solvates are crystalline solids containing either stoichiometricor non-stoichiometric amounts of a solvent incorporated within thecrystal structure. If the incorporated solvent is water, the solvatesare also commonly known as hydrates. Polymorphism refers to theoccurrence of different crystalline modifications of the same compoundor drug substance. Polymorphism in this commentary is defined as in theInternational Conference on Harmonization (ICH) Guideline Q6A(International Conference on Harmonization Q6A Guideline: Specificationsfor New Drug Substances and Products: Chemical Substances, October 1999,the disclosure of which is incorporated into this application byreference in its entirety), to include solvates and amorphous forms.

Stoichiometric solvates are preferably regarded as molecular compounds.The term preferably implies a fixed, although not necessarily integral,ratio of solvent to compound. Non-stoichiometric solvates preferably area type of inclusion compound. The most important feature of this classof solvates is that the structure is retained, while the solvent contentcan potentially take on all values between possibly zero and a multipleof the molar compound ratio. The amount of solvent in the structuredepends on the partial pressure of the solvent in the environment of thesolid and the temperature (see: U. J. Griesser, “The Importance ofSolvates” in R. Hilfiker (Editor) “Polymorphism in the PharmaceuticalIndustry”, Wiley VCH, 2006, the disclosure of which is incorporated intothis application in its entirety).

Polymorphs and/or solvates of a pharmaceutical solid can have differentchemical and physical properties such as melting point, hygroscopicity,chemical reactivity, apparent solubility, dissolution rate, optical andelectrical properties, vapor pressure and/or density. These propertiescan have a direct impact on the processability of drug substances andthe quality/performance of drug products, such as stability, dissolutionand/or bioavailability. A metastable pharmaceutical solid state form canchange crystalline structure or solvate/desolvate in response to changesin environmental conditions, processing, or over time.

The stability of an API is also important in pharmaceutical compositionsfor determining the shelf life of the particular medicament; the shelflife is the time period during which a drug product is expected toremain within the approved specification, provided that it is storedunder the defined conditions. Within the defined shelf life, amedicament can be administered without any risk for the patient. Highstability of a medicament in the abovementioned pharmaceuticalcompositions under various storage conditions is therefore an additionaladvantage for both the patient and the manufacturer.

Apart from the requirements indicated above, it should be generallyborne in mind that any change of the solid state form of apharmaceutical composition which is capable of improving its physicaland chemical stability gives a significant advantage over less stableforms of the same medicament. The aim of the invention is thus toprovide a new, stable solid material of the compoundcyclo-(Arg-Gly-Asp-DPhe-NMe-Val) which meets the stringent requirementsimposed on pharmaceutically active substances as mentioned above. Thus,one goal of the present invention is the provision of novel solidmaterials or forms of cyclo-(Arg-Gly-Asp-DPhe-NMe-Val) with improvedsolid-state properties.

It was now found that cyclo-(Arg-Gly-Asp-DPhe-NMe-Val) and especiallythe inner salt thereof can be obtained as a crystalline material andalso in special crystalline forms. Surprisingly a whole class of novelcrystalline forms of similar structural types (further on also to benamed pseudopolymorphic forms, PP) of cyclo-(Arg-Gly-Asp-DPhe-NMe-Val)have been found, which in fact exhibit beneficial solid state propertiesand preferably also possess advantageous combinations of beneficialsolid state properties, e.g. combined beneficial properties of the knownmaterial with beneficial properties of the new material according to theinvention.

Additionally, it was surprisingly found that different methods forobtaining the novel crystalline material preferably lead to differentcrystalline forms or modifications within said class of crystallineforms. These crystalline forms or modifications of the compoundcyclo-(Arg-Gly-Asp-DPhe-NMe-Val) and especially the inner salt thereofand the methods of making them are preferred the subject of the instantapplication.

Said novel solid material and said crystalline forms or modificationsshow valuable properties and advantages in comparison to the amorphousmaterials previously known, including, but not limited to a higherthermodynamic stability, reduced hygroscopicity, a higher crystallinity,improved handling properties, advantageous dissolution properties and/oran improved storage stability.

The compound{[(2S,5R,8S,11S)-5-Benzyl-11-(3-guanidino-propyl)-8-isopropyl-7-methyl-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-aceticacid} or cyclo-(Arg-Gly-Asp-DPhe-NMe-Val), also known under the INN(International Non-proprietary Name) Cilengitide, shows an advantageousbiological activity, including, but not limited to its integrininhibitory activity, anti-angiogenic activity and radiotherapy enhancingactivity, it is widely employed as an active principle in pharmaceuticalapplications.

For use as an active principle in pharmaceutical applications or shortfor use as API, factors such as high purity, excellent handlingproperties, sufficient stability and reliable manufacturing processesare crucial. Additionally, for such a peptidic compound having bothbasic and acidic centres or moieties, an exact stoichiometry in saltformation is another crucial factor and therefore a task for theproduction of the API. Acidic salts of cyclo-(Arg-Gly-Asp-DPhe-NMe-Val)have been found to be easily produced, but found to be less stable dueto acid catalysed degradation. Basic salts generally have been found topossess undesirable dissolution and handling properties. The previouslyknown and described amorphous forms of cyclo-(Arg-Gly-Asp-DPhe-NMe-Val)have been found to be unfavourably hygroscopic, one major drawback inthe production of dosage forms and also in the development of suitablepharmaceutical formulations.

Thus, a solid form with improved stability, improved handling, higherpurity and/or higher purification rate of the API, in comparison to theknown amorphous form, is generally highly desirous and a real need for areliable technical large-scale manufacture of the API. This is even moreso if a solid dosage formulation or suspension formulation of the APIhas to be provided.

Thus, subjects of the instant invention are:

A solid material of a compound according to formula I,

cyclo-(Arg-Gly-Asp-DPhe-NMeVal)  (I)

wherein said solid material comprises one or more crystalline forms ofthe compound of formula I, characterised by a unit cell with the latticeparameters

a=9.5±0.5 Å,

b=23.0±5.0 Å,

and

c=14.7±1.0 Å.

Said unit cell is preferably a crystallographic unit cell or acrystallographically determined unit cell.

In said unit cell, the angle α preferably is 90°±2°, the angle βpreferably is 90°±2° and/or the angle γ preferably is 90°±2°.

Preferably, the solid material comprises at least 10% by weight, morepreferably at least 30% by weight, even more preferably 60% by weightand especially at least 90% by weight or at least 95% by weight, of oneor more crystalline forms of the compound of formula I as defined aboveand/or below. For example, the solid material comprises about 25, about50, about 75, about 95, about 99 or about 100% by weight of one or morecrystalline forms of the compound of formula I as defined above and/orbelow.

Especially preferably, the solid material comprises at least 10 mole %,more preferably at least 30 mole %, even more preferably 60 mole % andespecially at least 90 mole % or at least 95 mole %, of one or morecrystalline forms of the compound of formula I as defined above and/orbelow. For example, the solid material comprises about 25, about 50,about 75, about 95, about 99 or about 100 mole % of one or morecrystalline forms of the compound of formula I as defined above and/orbelow.

The percentages by weight given for the solid material according to theinvention preferably relate to the ratio between the weight of the oneor more crystalline forms as defined above/below contained in said solidmaterial and the total amount by weight of the compound of formula Icontained in said solid material. In other words, the percentages byweight given preferably are the weight percentages of the sum of the oneor more crystalline forms as defined above and/or below based on thetotal amount by weight of the compound of formula I. Thus, the weightpercentages given for the content of the one or more crystalline formswith in the solid material according to the invention are preferablyindependent of the amount or content of compounds or impurities otherthan the compound according to formula I contained in said solidmaterial. Thus, the percentages by weight given for the solid materialare preferably corrected for the contained solvent molecules, i.e. thepercentages by weight given for the solid material are preferablyindependent of or calculated without the solvent molecules in said solidmaterial.

The mole percentages (mole %) given for the solid material according tothe invention preferably relate to the molar ratio between the one ormore crystalline forms as defined above/below contained in said solidmaterial and the total molar amount of the compound of formula Icontained in said solid material. In other words, the mole percentagesgiven preferably are the mole percentages of the sum of the one or morecrystalline forms as defined above and/or below based on the total molaramount of the compound of formula I. Thus, the mole percentages givenfor the content of the one or more crystalline forms with in the solidmaterial according to the invention are preferably independent of theamount or content of compounds or impurities other than the compoundaccording to formula I contained in said solid material. Thus, the molepercentages (mole %) given for the solid material are preferablycorrected for the contained solvent molecules, i.e. the mole percentages(mole %) given for the solid material are preferably independent of orcalculated without the solvent molecules in said solid material.

One or more crystalline forms in regard to said solid materialpreferably means that the solid material comprises at least one or morecrystalline form or modification of the compound of formula I having aunit cell within the lattice parameters as defined above and/or below,or that the solid material comprises mixtures of two or more, forexample two or three, crystalline forms or modifications of the compoundof formula I, each having a unit cell within the lattice parameters asdefined above and/or below.

Preferably, the solid material comprises one, two, three or fourcrystalline forms of the compound of formula I as defined above and/orbelow.

More preferably, the solid material comprises one or more, preferablyone, two, three or four, even more preferably one or two, crystallineforms of the compound of formula I, each having a unit cell with latticeparameters (ULP) selected from a group consisting of

ULP1:

a1=9.5±0.5 Å,

b1=26.0±1.5 Å,

and

c1=14.3±0.7 Å,

and

ULP2:

a2=9.8±0.5 Å,

b2=20.0±1.5 Å,

and

c2=15.4±0.7 Å.

More preferably, the solid material comprises one or more, preferablyone, two, three or four, even more preferably one or two, crystallineforms of the compound of formula I, each having a unit cell with latticeparameters (ULP) selected from a group consisting of

ULP1:

a1=9.5±0.3 Å,

b1=26.0±1.0 Å,

and

c1=14.3±0.5 Å,

and

ULP2:

a2=9.8±0.3 Å,

b2=20.0±1.0 Å,

and

c2=15.4±0.5 Å.

In the unit cell with lattice parameters ULP1 and/or ULP2, the angle αpreferably is 90°±2°, the angle β preferably is 90°±2° and/or the angleγ preferably is 90°±2°.

Preferably, the unit cell with lattice parameters ULP1 can becharacterised, alternatively or additionally, preferably additionally,by a content of about 4 molecules of the compound of formula I withinsaid unit cell.

In the unit cell with lattice parameters ULP2, the angle α preferably is90°±0.5°, the angle β preferably is 90°±0.5° and/or the angle γpreferably is 90°±0.5°. In the unit cell with lattice parameters ULP2,the angles α, β and γ more preferably are 90°±0.1°.

Preferably, the unit cell with lattice parameters ULP2 can becharacterised, alternatively or additionally, preferably additionally,by a content of about 4 molecules of the compound of formula I withinsaid unit cell.

More preferably, the solid material comprises one or more, preferablyone, two, three or four, even more preferably one or two, crystallineforms of the compound of formula I, selected from

crystalline form A1, characterised by a unit cell with the latticeparameters a=9.8±0.1 Å, b=19.5±0.5 Å, and c=15.4±0.1 Å,crystalline form S1, characterised by a unit cell with the latticeparameters a=9.4±0.1 Å, b=25.9±0.5 Å, and c=14.1±0.1 Å,crystalline form S2, characterised by a unit cell with the latticeparameters a=9.3±0.1 Å, b=26.6±0.5 Å, and c=14.7±0.1 Å, andcrystalline form S3, characterised by a unit cell with the latticeparameters a=9.6±0.1 Å, b=25.9±0.5 Å, and c=13.9±0.1 Å.

More preferably, the solid material comprises one or more, preferablyone, two, three or four, even more preferably one or two, crystallineforms of the compound of formula I, selected from

crystalline form A1, characterised by a unit cell with the latticeparameters a=9.8±0.1 Å, b=19.5±0.5 Å, and c=15.4±0.1 Å, preferably withα=β=γ=90°±1° and especially with α=β=γ=90°;crystalline form S1, characterised by a unit cell with the latticeparameters a=9.4+0.1 Å, b=25.9±0.5 Å, and c=14.1±0.1 Å, preferably withα=β=γ=90°±2°, and especially with α=90°±1°, β=91°±1, γ=90°±1° andespecially with α=90°, β=91.2°, γ=90°;crystalline form S2, characterised by a unit cell with the latticeparameters a=9.3±0.1 Å, b=26.6±0.5 Å, and c=14.7±0.1 Å, preferably withα=β=γ=90°±1° and especially with α=β=γ=90°; andcrystalline form S3, characterised by a unit cell with the latticeparameters a=9.6±0.1 Å, b=25.9±0.5 Å, and c=13.9±0.1 Å, preferably withα=β=γ=90°±1° and especially with α=β=γ=90°.

Preferably, the crystalline forms S1, S2 and S3 can be characterised,alternatively or additionally, preferably additionally, by a content ofabout 4 molecules of the compound of formula I within said unit cells.

The crystalline forms S1, S2 and S3 are preferably further characterisedas solvates.

In the context of the present invention, solvates preferably arecrystalline solid adducts containing either stoichiometric ornon-stoichiometric amounts of a solvent incorporated within the crystalstructure, i.e. the solvent molecules preferably form a part of thecrystal structure. If the incorporated solvent is water, the solvatesare also commonly known as hydrates.

As a result, the solvent in the solvates preferably forms a part of thecrystal structure and thus is in general detectable by X-ray methods andpreferably detectable by X-ray methods as described herein.

In general, for a given crystal structure, there is an upper limit forthe amount of solvent incorporated into said structure (without inducinga transition into another crystal structure). In some cases, however, itis possible to remove at least a part of the incorporated solvent byphysical treatment of the crystal structure, for example by dryingprocedures, e.g. by storage at elevated temperatures (but preferablybelow a melting or other phase transition point), and/or reducedpressure, preferably including applying vacuum and reduced partialpressure. In principal in such cases, the solvent can be partly or fullyremoved from the crystal structure, thus introducing voids into saidcrystal structure. The likelihood of a phase transition and/orpolymorphic transition, e.g. the transition into a different polymorphicform or especially the transition into an amorphous form, a solvate orhydrate containing less solvent or water molecules or an anhydrate form,increases with the amount of incorporated solvent converging to zero.

In such cases, the solvent contained and/or the amount thereof and thusthe composition of the respective solvates or solvate structure canpreferably be varied by adequate treatment, including, but not limitedto conditioning and/or recrystallisation. For example, one solvent canbe partly or fully removed from such a solvate, one solvent can bepartly or fully substituted by a different solvent in such a solvateand/or the amount of solvent in such a solvate can be increased ordecreased. Thus, a solvate containing a specific solvent can potentiallybe transformed into a solvate containing a solvate mixture, and viceversa.

Conditioning in this regard preferably relates to physical treatments,wherein the original crystal structure of the respective solvate isessentially retained. Suitable methods, and means and/or parameters forconditioning of solvates are in principle known to the skilled artisan.Examples of suitable conditioning methods are disclosed in the instantapplication and preferably include, but are not limited to, exposure tosolvent vapour, exposure to thermal conditions (for example bydifferential scanning calorimetry, thermogravimetry and/or storage atspecific temperatures or temperature gradients), slurrying (e.g. formingand/or treating a suspension of a solvate in a liquid that comprises orone or more solvents), exposure to variable partial pressure of one ormore solvents, exposure to specific partial pressure and/or specificpartial pressure gradients of one or more solvents, and combinationsthereof. For example the slurrying and/or the exposure to variablepartial pressure of one or more solvents can be realised at specifictemperatures or temperature gradients. A preferred form of conditioningis solvating or desolvating. Slurries and working techniques forslurries or slurrying are known in the art, for example from Martyn D.Ticehurst,* Richard A. Storey, Claire Watt, International Journal ofPharmaceutics 247 (2002) 1-10, the disclosure of which is incorporatedinto this application in its entirety.

Additionally or alternatively, the solvent contained and/or the amountthereof and thus the composition of the respective solvates or solvatestructure can preferably be also varied by recrystallisation, especiallyby recrystallisation from a different solvent or solvent mixture,provided the original crystal structure of the solvate is reproduced oressentially reproduced.

In this regard, solvate preferably means that the unit cell orcrystallographic unit cell contains an about stoichiometric—integer ornon integer—amount of solvent molecules of one or more solvents permolecule of the compound of formula I contained in said unit cell. Theabout stoichiometric amount of solvent molecules in said unit cell permolecule of the compound of formula I contained in said unit cellpreferably lies in the range of about 0.01 solvent molecules to about 8solvent molecules, more preferably in the range of about 0.1 solventmolecules to about 7 solvent molecules and even more preferably in arange of about 1.5 solvent molecules up to about 4.5 solvent molecules,for example about 0.1 solvent molecules, about 0.5 solvent molecules,about 1.5 solvent molecules, about 3 solvent molecules, about 4 solventmolecules or about 7 solvent molecules per molecule of the compoundaccording to formula I. Especially preferred are solvates having aboutfour solvent molecules per molecule of the compound according to formulaI contained in said unit cell. If the unit cell or crystallographic unitcell contains about 4 solvent molecules of one or more solvents permolecule of the compound of formula I contained in said unit cell, it ispreferably regarded as a tetrasolvate, and if it contains about 7solvent molecules of one or more solvents per molecule of the compoundof formula I contained in said unit cell, it is preferably regarded as aheptasolvate.

In this regard, solvate preferably means that the unit cell orcrystallographic unit cell contains an about stoichiometric, preferablyinteger or non-integer, more preferably about integer, amount of solventmolecules of one or more solvents per molecule of the compound offormula I contained in said unit cell. The about stoichiometric amountof solvent molecules in said unit cell per molecule of the compound offormula I contained in said unit cell preferably lies in the range ofabout 0.5 solvent molecules to about 6 solvent molecules, morepreferably in the range of about 0.5 solvent molecules to about 4.5solvent molecules and even more preferably in a range of about 1.5solvent molecules up to about 4 solvent molecules per molecule of thecompound according to formula I contained in said unit cell, for exampleabout 0.5 solvent molecules, about 1.5 solvent molecules, about 4solvent molecules or about 6 solvent molecules per molecule of thecompound according to formula I contained in said unit cell. Especiallypreferred are solvates having about four solvent molecules per moleculeof the compound according to formula I contained in said unit cell. Ifthe unit cell or crystallographic unit cell contains about 4 solventmolecules of one or more solvents per molecule of the compound offormula I contained in said unit cell, it is preferably regarded as atetrasolvate.

Preferred solvents or solvent molecules in this regard are selected fromthe group consisting of water and alcohols, and more preferably selectedfrom the group consisting of water, methanol and ethanol.

For example, if the unit cell of a crystalline form contains onemolecule of the compound according to the formula I and about foursolvent molecules, said form is preferably to be regarded as atetrasolvate. If the unit cell of a crystalline form contains twomolecules of the compound of formula I and about eight solventmolecules, said form is preferably also to be regarded as atetrasolvate. If the unit cell of a crystalline form contains fourmolecules of the compound of formula I and about sixteen solventmolecules, said form is preferably also to be regarded as atetrasolvate. The same holds true, if the unit cell of a crystallineform contains 2½ molecules of the compound according to a formula I andabout 10 solvent molecules.

Thus, solvate more preferably means that the respective crystalline formcontains an about stoichiometric—integer or non-integer—amount ofsolvent molecules of one or more solvents per molecule of the compoundof formula I. The about stoichiometric amount of (the one or more)solvent molecules in said solvate preferably lies in the range of about0.1 solvent molecules to about 7 solvent molecules per molecule of thecompound according to formula I, more preferably in the range of about0.5 solvent molecules per molecule of the compound according to formulaI up to about 4.5 solvent molecules per molecule of the compoundaccording to formula I and even more preferably in a range of about 1.5solvent molecules per molecule of the compound according to formula I upto about 4 solvent molecules per molecule of the compound according toformula I, for example about 0.5 solvent molecules, about 1.5 solventmolecules, about 3 solvent molecules, about 4 solvent molecules or about7 solvent molecules per molecule of the compound according to formula Icontained in said unit cell. Especially preferred are solvates havingabout four solvent molecules per molecule of the compound according toformula I.

Thus, solvate more preferably means that the respective crystalline formcontains an about stoichiometric amount of solvent molecules of one ormore solvents per molecule of the compound of formula I. The aboutstoichiometric amount of (the one or more) solvent molecules in saidsolvate preferably lies in the range of about 0.5 solvent molecules toabout 6 solvent molecules per molecule of the compound according toformula I, more preferably in the range of about 0.5 solvent moleculesup to about 4.5 solvent molecules per molecule of the compound accordingto formula I and even more preferably in a range of about 1.5 solventmolecules per molecule of the compound according to formula I up toabout 4 solvent molecules per molecule of the compound according toformula I, for example about 0.5 solvent molecules, about 1.5 solventmolecules, about 4 solvent molecules or about 6 solvent molecules permolecule of the compound according to formula I. Especially preferredare solvates having about four solvent molecules per molecule of thecompound according to formula I.

More preferred stoichiometries of the solvate are defined as depicted inthe area shaded in grey in the graph below (Graph I):

In this graph x is the number of water molecules per molecule of thecompound according to formula I (which might be integer or non-integer)and y is the number of molecules of alcohol, preferably either methanolor ethanol or mixtures thereof, and might be integer or non-integer.Accordingly, preferably the number of alcohol molecules per molecule ofthe compound according to formula I is in between 0 and about 4, andpreferably between 0.1 and 4, and the number of water molecules is inbetween 0 and about 4, and preferably between 0.1 and 4.

Even more preferred stoichiometries of the solvate are defined asdepicted in the area shaded in grey in the graph below (Graph II):

In this graph x is the number of water molecules per molecule of thecompound according to formula I (which might be integer or non-integer)and y is the number of molecules of alcohol, preferably either methanolor ethanol or mixtures thereof, and might be integer or non-integer.Accordingly, preferably the number of alcohol molecules per molecule ofthe compound according to formula I is in between 0 and about 2, andpreferably between 0.1 and 2, and the number of water molecules is inbetween 0 and about 4, and preferably between 0.1 and 4.

Sill even more preferred stoichiometries of the solvate are defined asdepicted in the area shaded in grey in the graph below (Graph III):

In this graph x is the number of water molecules per molecule of thecompound according to formula I (which might be integer or non-integer)and y is the number of molecules alcohol, preferably either methanol orethanol or mixtures thereof, and might be integer or non-integer.Accordingly, preferably the number of alcohol molecules per molecule ofthe compound according to formula I is in between 0 and about 1, morepreferably between 0.1 and 1, and the number of water molecules is inbetween 0 and about 4, more preferably in between 0.1 and 4.

Especially preferred solvents or solvent molecules in this regard areselected from the group consisting of water and alcohols, and morepreferably selected from the group consisting of water, methanol andethanol.

Solvates of the compound according to formulae I having the compositionor stoichiometry as described in Graph I, Graph II and/or Graph III andpreferably also as described in the paragraphs relating thereto,respectively, are especially preferred subject of the instant invention.The above and/or below described solvates are especially preferredexamples for said solvates having a composition or stoichiometry withinthe ranges as described in Graph I, Graph II and/or Graph III and thusare also especially preferred subjects of the instant invention.

Based on the description given above and/or below and preferably also onthe description of the solvates or crystalline forms S1, S2 and/or S3,it becomes apparent that the solvates or crystalline forms characterisedby a unit cell with the unit cell parameters ULP1 can comprise 0 toabout 4 solvent molecules per molecule of the compound of formula Iwithin said unit cell, more preferably 0.01 to about 4 solvent moleculesper molecule of the compound of formula I within said unit cell andespecially 0.5 to 4 solvent molecules per molecule of the compound offormula I within said unit cell.

Thus, a common feature or characteristic of the solvates or crystallineforms characterised by a unit cell with the unit cell parameters ULP1 isthe upper limit of the solvent content of about four molecules of one ormore solvents, preferably solvents as described herein, per molecule ofthe compound according to formula I. In accordance with the art, thesolvates or crystalline forms characterised by an upper limit of thesolvent content of about four molecules of one or more solvents permolecule of the compound of formula I in said unit cell are preferablyreferred to as tetrasolvates.

However, as is extensively described herein, said solvates orcrystalline forms characterised by a unit cell with the unit cellparameters ULP1 can be desolvated to a solvent content of about 3 orless solvent molecules per molecule of the compound of formula I withinsaid unit cell, to a solvent content of about 2 or less solventmolecules per molecule of the compound of formula I within said unitcell, to a solvent content of about 1 or less solvent molecules permolecule of the compound of formula I within said unit cell, or even toa solvent content of close to 0.5, 0.1 or 0 solvent molecules permolecule of the compound of formula I within said unit cell. Thesedesolvates of the solvates or crystalline forms characterised by a unitcell with the unit cell parameters ULP1 are also at preferred subject ofthe instant invention.

As a result, the term “tetrasolvate” and/or “tetrahydrate” as usedherein preferably also includes the partly or totally desolvated formsof said tetrasolvates and/or tetrahydrates, preferably as long as therespective crystal structure of the original tetrasolvate ortetrahydrate is retained or essentially retained.

As a further result, the term “tetrasolvate” as used herein preferablyalso includes alcohol solvates (or alcoholates) or mixed water-alcoholsolvates, preferably including, but not limited to theDihydrate-dialcoholate, the Dihydrate-alcoholate and theDihydrate-monoalcoholate, and/or the partly or totally desolvated formsthereof, preferably as long as the respective crystal structure of theoriginal tetrasolvate and especially preferably the original crystalstructure of the tetrahydrate S3 is retained or essentially retained.

As a further result, the term “tetrasolvate” as used herein preferablyalso includes alcohol solvates (or alcoholates) or mixed water-alcoholsolvates, preferably including, but not limited to theDihydrate-dialcoholate, the Dihydrate-alcoholate, theDihydrate-monoalcoholate and the Dialcoholate (preferably given by theformula (Cil)₁(Alcohol)₂(H₂O)₀), and/or the partly or totally desolvatedforms thereof, preferably as long as the respective crystal structure ofthe original tetrasolvate and especially preferably the original crystalstructure of the tetrahydrate S3 is retained or essentially retained.Thus, all crystalline forms within the unit cell parameters according toULP1 as defined herein are preferably regarded as tetrasolvatesaccording to the instant invention.

Preferably, the Dialcoholates according to the invention are to beregarded as tetrasolvates and/or desolvates thereof, which preferablycontain about two alcohol molecules per molecule of the compound offormula I, but which preferably contain less than one molecule, morepreferably less than 0.5 molecules and especially less than 0.1 watermolecules per molecule of the compound of formula I. Thus, preferreddialcoholates according to the invention contain about 4 molecules ofthe compound of formula I and about 8 molecules of alcohol in the unitcell, but preferably less than one molecule of water. Preferably, thealcohol in said dialcoholates is selected from methanol and ethanol andmixtures thereof. Thus, the dialcoholates according to the invention canpreferably also be regarded as desolvates or more specifically asdehydrates of the Dihydrate-dialcoholates according to the invention.

The crystalline form A1 preferably is further characterised as ananhydrate or ansolvate.

In this regard, anhydrate or ansolvate preferably means that the unitcell is free or essentially free of about stoichiometric amounts ofsolvent molecules of one or more solvents. In this regard, anhydrate oransolvate more preferably means that the unit cell is essentially freeof water and solvent molecules. Essentially free of solvent molecules inthis regard preferably means that the amount of solvent molecules in theunit cell is lower than 0.5, more preferably lower than 0.1, even morepreferably lower than 0.01 and especially lower than 0.001.

Since both ansolvates and an anhydrates are characterised by the absenceof the respective solvents and thus characterised by the absence of anysolvent, the terms anhydrate and ansolvate are preferably to be regardedas synonyms in the context of the present invention.

The amount of molecules in the unit cell is preferably determined bycrystallographic methods, more preferably by single crystal X-raydiffraction and/or powder X-ray diffraction.

Alternatively, the amount of solvent in said crystalline forms, saidsolvates and/or in the respective unit cell can be determined orestimated by elemental analysis, gas chromatography or Karl-Fischertitration. In this context, essentially free of solvent moleculespreferably means a solvent content of less than 5%, even more preferablyless than 2%, even more preferably less than 1% and especially less than0.1%, for example 5% to 0.1% or 2% to 0.01%. In this regard, the givenpercentages (%) are preferably selected from mole % and % by weight andespecially preferably are % by weight.

The crystalline forms A1, S2 and/or S3 are preferably furthercharacterised by orthorhombic unit cell.

The crystalline form S1 is preferably further characterised by amonoclinic unit cell.

The unit cell and the lattice parameters, preferably including, but notlimited to a, b, c, α, β and/or γ, are crystallographic parameters knownto the ones skilled in the art. Hence, they can be determined accordingto methods known in the art. The same preferably holds true for theorthorhombic and/or monoclinic form of the unit cell.

The above given unit cells and the lattice parameters relating theretoare preferably determined by X-Ray Diffraction, more preferably SingleCrystal X-Ray Diffraction and/or Powder X-Ray Diffraction, according tostandard methods, for example methods or techniques as described in theEuropean Pharmacopeia 6^(th) Edition chapter 2.9.33, and/or as describedin Rolf Hilfiker, ‘Polymorphism in the Pharmaceutical Industry’,Wiley-VCH. Weinheim 2006 (Chapter 6: X-Ray Diffraction), and/or H. G.Brittain, ‘Polymorphism in Pharmaceutical Solids, Vol. 95, Marcel DekkerInc., New York 1999 (Chapter 6 and references therein).

Alternatively preferably, the above given unit cells and the latticeparameters relating thereto can be obtained by single crystal X-Ray,optionally together with additional structure data, preferably conducted

on a XCalibur diffractometer from Oxford Diffraction equipped withgraphite monochromator and CCD Detector using Mo K_(α) radiation,preferably at a temperature of 298K±5 K; and/oron a CAD4 four circle diffractometer from Nonius equipped with graphitemonochromator and scintillation counter using Mo K_(α) radiation,preferably at a temperature of 298 K±5 K.

The above given unit cells and the lattice parameters relating theretoare preferably determined by X-Ray Diffraction, more preferably PowderX-Ray

Diffraction, according to standard methods, for example methods ortechniques as described in the European Pharmacopeia 6^(th) Editionchapter 2.9.33, and/or as described in Rolf Hilfiker, ‘Polymorphism inthe Pharmaceutical Industry’, Wiley-VCH. Weinheim 2006 (Chapter 6: X-RayDiffraction), and/or H. G. Brittain, ‘Polymorphism in PharmaceuticalSolids, Vol. 95, Marcel Dekker Inc., New York 1999 (Chapter 6 andreferences therein).

Higher contents of the one or more crystalline forms as defined aboveand/or below in the solid material as described above and/or below aregenerally preferred.

A solid material as described above and/or below, essentially consistingof one or more crystalline forms of the compound of formula I,characterised by a unit cell with the lattice parameters

a=9.5±0.5 Å,

b=23.0±5.0 Å,

and

c=14.7±1.0 Å,

and especially characterised as described above and/or below.

Essentially consisting of one or more crystalline forms of the compoundof formula I preferably means that the compound of formula I containedin said solid material is essentially selected from said one or morecrystalline forms of the compound of formula I, or in other words, thatthe one or more crystalline forms in said solid form provide for theessential amount of compound of formula I in said solid form. Morespecifically, essentially in this regard preferably means that the oneor more crystalline forms in said solid form provide for 90% or more,preferably 95% or more, even more preferably 99% or more and especially99.9% or more, of the amount of compound of formula I in said solidform. In this regard, the given percentages (%) are preferably selectedfrom mole % and % by weight and especially preferably are mole %.

Said amounts can be provided by one single crystalline form as describedherein, or by mixtures of two or more crystalline forms as describedherein. Preferably, said amounts are provided by one single crystallineform as described herein. More preferably, said amounts are provided byone single crystalline form, selected from crystalline form A1,crystalline form S1, crystalline form S2 and crystalline form S3 asdescribed herein.

If the solid material comprises two or more of the crystalline forms asdescribed herein, one of these crystalline forms is preferably the majorcrystalline form and the one or more further crystalline forms presentare present in minor amounts. The major crystalline form preferablyprovides for 60% by weight or more, more preferably 75% or more, evenmore preferably 90% or more and especially 95 or 99% or more, of thetotal amount of the crystalline forms present. In this regard, the givenpercentages (%) are preferably selected from mole % and % by weight andespecially preferably are mole %.

If not specified otherwise, percentages (or %) given herein forcompounds and/or solvents are preferably either percentages by weight ormole percent, preferably mole percent. Since the content of the one ormore crystalline forms in the solid material according to the invention,and, if applicable, the ratio of two or more crystalline forms in thesolid material according to the invention, can advantageously bedetermined via methods including, but not limited to, PowderX-Ray-Diffraction, Raman-spectroscopy and infrared spectroscopy, andmore preferably are determined by Powder X-Ray-Diffraction,Raman-spectroscopy and/or infrared spectroscopy, percent values relatedthereto are especially preferably mole percent values, if not explicitlystated otherwise.

Preferably, if not specified otherwise, percentages (or %) given herein

-   -   i) for spectral data, such as transmission, especially IR        transmission, Raman intensity;    -   ii) Powder X-Ray diffraction intensities (PXRD intensities);        and/or    -   iii) analytical parameters, such as relative humidity (rh or        r.h.), and the like,        are preferably relative percentages (i.e. percent of the        respective maximum value).

A preferred subject of the invention are the one or more crystallineforms of the compound of formula I as described herein and especially asdescribed above and/or below.

Preferably, the one or more crystalline forms of the compound of formulaI are selected from the crystalline forms as described above and/orbelow having a monoclinic unit cell or a orthorhombic unit cell.

Preferably, the one or more crystalline forms of the compound of formulaI are selected from anhydrates or ansolvates and solvates.

Preferably, the solvates are selected from hydrates, methanolates(methanol solvates), and ethanolates (ethanol solvates), and mixturesthereof. Said mixtures are preferably selected from mixed water-methanolsolvates, mixed water ethanol solvates, mixed methanol-ethanol solvates,and mixed methanol-ethanol-water-solvates.

Preferably, the anhydrates or ansolvates according to the invention andespecially the crystalline form A1 can be characterised, alternativelyor additionally, by a melting/decomposition temperature of >282° C.,more preferably 288±5° C. or higher, and especially 288±5° C.

The melting/decomposition temperatures and/or thermal behaviorsdescribed herein are preferably determined by DSC (Differential Scanningcalorimetry) and TGA (ThermoGravimetric Analysis). DSC and/or TGAmethods or generally thermoanalytic methods and suitable devices fordetermining them are known in the art, for examples from EuropeanPharmacopeia 6^(th) Edition chapter 2.02.34, wherein suitable standardtechniques are described. More preferably, for the melting/decompositiontemperatures or behaviors and/or the thermoanalysis in generally, aMettler Toledo DSC 821 and/or Mettler Toledo TGA 851 are used,preferably as described in the European Pharmacopeia 6^(th) Editionchapter 2.02.34.

The DSC and TGA measurements showing the thermal analysis(Mettler-Toledo DSC 821, 5 K/min, nitrogen purge gas 50 ml/min;Mettler-Toledo TGA 851, K/min, nitrogen purge gas 50 ml/min) and themelting/decomposition temperature given above is shown in FIG. 1 andFIG. 2.

Preferably, the anhydrates or ansolvates according to the invention andespecially the crystalline form A1 can be characterised, alternativelyor additionally, by Powder X-Ray Diffraction and more preferably by thePowder X-Ray Diffraction pattern comprising one or more of the PowderX-ray peaks given below, more preferably comprising 6 or more of thePowder X-ray peaks given below, even more preferably 8 or more of thePowder X-ray peaks given below, and especially comprising all of the ofthe Powder X-ray peaks given below:

a) D ± 0.1 °2 θ (Cu-Kα₁, Miller indizes No. [Å] radiation) ± 0.1° h k l1 12.08 7.3 0 1 1 2 9.75 9.1 0 0 2 4 8.24 10.7 1 1 0 7 6.91 12.8 1 0 2 86.05 14.6 1 2 0 9 4.88 18.2 0 0 4 10 4.54 19.5 2 1 1 11 4.43 20.0 1 3 112 4.37 20.2 2 0 2 13 4.21 21.1 2 1 2 14 4.12 21.2 2 2 0 15 3.79 23.4 21 3or more preferably

b) D ± 0.1 °2 θ (Cu-Kα₁, Miller indizes No. [Å] radiation) ± 0.1° h k l1 12.08 7.3 0 1 1 2 9.75 9.1 0 0 2 4 8.24 10.7 1 1 0 7 6.91 12.8 1 0 2 86.05 14.7 0 2 2 9 4.88 18.2 0 0 4 10 4.54 19.5 2 1 1 11 4.43 20.0 1 3 112 4.37 20.3 2 0 2 13 4.21 21.1 2 1 2 14 4.12 21.5 2 2 0 15 3.79 23.4 21 3

Preferably, the anhydrates or ansolvates according to the invention andespecially the crystalline form A1 can be characterised, alternativelyor additionally, by Powder X-Ray Diffraction and more preferably by thePowder X-Ray Diffraction pattern comprising the Powder X-ray peaks givenbelow:

a) D °2 θ (Cu-Kα₁, Miller indizes No. [Å] radiation) ± 0.1° h k l 112.08 7.3 0 1 1 2 9.75 9.1 0 0 2 4 8.24 10.7 1 1 0 7 6.91 12.8 1 0 2 86.05 14.6 1 2 0 9 4.88 18.2 0 0 4 10 4.54 19.5 2 1 1 11 4.43 20.0 1 3 112 4.37 20.2 2 0 2 13 4.21 21.1 2 1 2 14 4.12 21.2 2 2 0 15 3.79 23.4 21 3or more preferably

b) D °2 θ (Cu-Kα₁, Miller indizes No. [Å] radiation) ± 0.1° h k l 112.08 7.3 0 1 1 2 9.75 9.1 0 0 2 4 8.24 10.7 1 1 0 7 6.91 12.8 1 0 2 86.05 14.7 0 2 2 9 4.88 18.2 0 0 4 10 4.54 19.5 2 1 1 11 4.43 20.0 1 3 112 4.37 20.3 2 0 2 13 4.21 21.1 2 1 2 14 4.12 21.5 2 2 0 15 3.79 23.4 21 3

Preferably, the anhydrates or ansolvates according to the invention andespecially the crystalline form A1 can be characterised, alternativelyor additionally, by Powder X-Ray Diffraction and more preferably by thePowder X-Ray Diffraction pattern comprising one or more of the PowderX-ray peaks given below, more preferably comprising 10 or more of thePowder X-ray peaks given below, even more preferably 12 or more of thePowder X-ray peaks given below, and especially comprising all of the ofthe Powder X-ray peaks given below:

a) D ± 0.1 °2 θ (Cu-Kα₁, Miller indizes No. [Å] radiation) ± 0.1° h k l1 12.08 7.3 0 1 1 2 9.75 9.1 0 0 2 3 8.75 10.1 1 0 1 4 8.24 10.7 1 1 0 57.69 11.5 0 2 0 6 7.16 12.4 0 2 1 7 6.91 12.8 1 0 2 8 6.05 14.6 1 2 0 94.88 18.2 0 0 4 10 4.54 19.5 2 1 1 11 4.43 20.0 1 3 1 12 4.37 20.2 2 0 213 4.21 21.1 2 1 2 14 4.12 21.2 2 2 0 15 3.79 23.4 2 1 3or more preferably

b) °2θ (Cu—Kα₁ Miller D ± 0.1 radiation) ± indizes No. [Å] 0.1° h k l 112.08 7.3 0 1 1 2 9.75 9.1 0 0 2 3 8.75 10.1 1 0 1 4 8.24 10.7 1 1 0 57.69 11.5 0 2 0 6 7.16 12.4 0 2 1 7 6.91 12.8 1 0 2 8 6.05 14.7 0 2 2 94.88 18.2 0 0 4 10 4.54 19.5 2 1 1 11 4.43 20.0 1 3 1 12 4.37 20.3 2 0 213 4.21 21.1 2 1 2 14 4.12 21.5 2 2 0 15 3.79 23.4 2 1 3

The Powder X-Ray Diffraction and more preferably the Powder X-RayDiffraction pattern is preferably performed or determined as describedherein and especially performed or determined by standard techniques asdescribed in the European Pharmacopeia 6^(th) Edition chapter 2.9.33,and is even more preferably obtained with the parameters Cu—Kα₁radiation and/or λ=1.5406 Å, preferably on a Stoe StadiP 611 KLdiffractometer.

FIG. 3 shows the Powder X-ray diffractogram of crystalline form A1

Preferably, the anhydrates or ansolvates according to the invention andespecially the crystalline form A1 can be characterised, alternativelyor additionally, by Single Crystal X-Ray Structure Data, for exampleSingle Crystal X-Ray Structure Data obtained on a diffractometerpreferably equipped with a graphite monochromator and CCD Detector,preferably using Mo K_(α) radiation, preferably at a temperature of 298K±5 K, and even more preferably on a XCalibur diffractometer from OxfordDiffraction equipped with graphite monochromator and CCD Detector usingMo K_(α) radiation at about 298 K.

According to the Single Crystal X-Ray Structure Data obtained, theanhydrate of the compound of formula I and especially crystalline formA1 crystallises in the orthorhombic space group P 2₁ 2₁ 2₁ with thelattice parameters a=9.8 Å, b=15.4 Å, c=19.5 Å (±0.1 Å) and the unitcell volume is preferably 2940 (±10) Å³

From the single crystal structure it is obvious that form A1 representsan anhydrate or ansolvate.

The Single Crystal X-Ray Structure is depicted in FIG. 4.

Preferably, the anhydrates and ansolvates according to the invention andespecially the crystalline form A1 can be characterised, alternativelyor additionally, by the infrared-spectroscopy data comprising one ormore of the band positions (±2 cm⁻¹) given below, more preferablycomprising 6 or more of the band positions (±2 cm⁻¹) given below, evenmore preferably comprising 9 or more of the band positions (±2 cm⁻¹)given below, and especially comprising all the band positions (±2 cm⁻¹)given below, preferably together with the relative intensities given inbrackets:

3431 cm⁻¹ (s), 3339 cm⁻¹ (s), 3189 cm⁻¹ (s), 2962 cm⁻¹ (m), 2872 cm⁻¹(m), 1676 cm⁻¹ (s), 1660 cm⁻¹ (s), 1617 cm⁻¹ (s), 1407 cm⁻¹ (s), 1316cm⁻¹ (m), 1224 cm⁻¹ (m), 1186 cm⁻¹ (m), 711 cm⁻¹ (m).

More preferably, the anhydrates and ansolvates according to theinvention and especially the crystalline form A1 can be characterised,alternatively or additionally, by the infrared-spectroscopy datacomprising one or more of the band positions (±2 cm⁻¹) given below, morepreferably comprising 9 or more of the band positions (±2 cm⁻¹) givenbelow, even more preferably comprising 12 or more of the band positions(±2 cm⁻¹) given below, and especially comprising all the band positions(±2 cm⁻¹) given below, preferably together with the relative intensitiesgiven in brackets:

3431 cm⁻¹ (s), 3339 cm⁻¹ (s), 3189 cm⁻¹ (s), 3031 cm⁻¹ (m), 2962 cm⁻¹(m), 2872 cm⁻¹ (m), 1676 cm⁻¹ (s), 1660 cm⁻¹ (s), 1617 cm⁻¹ (s), 1539cm⁻¹ (s), 1493 cm⁻¹ (s), 1407 cm⁻¹ (s), 1358 cm⁻¹ (m), 1316 cm⁻¹ (m),1247 cm⁻¹ (m), 1224 cm⁻¹ (m), 1186 cm⁻¹ (m), 994 cm⁻¹ (w), 921 cm⁻¹ (w),711 cm⁻¹ (m), 599 cm⁻¹ (m).

The relative intensities given in brackets are preferably defined asfollows: *“s”=strong (transmittance preferably ≦50%), “m”=medium(preferably 50%<transmittance≦70%), “w”=weak (transmittance preferably>70%)

The IR or FT-IR spectrum is preferably obtained using a KBr pellet assample preparation technique.

The IR-spectroscopy data is preferably obtained by FT-IR-spectroscopy,The IR-spectroscopy data or FT-IR-spectroscopy data is preferablyobtained by standard techniques as described in the EuropeanPharmacopeia 6^(th) Edition chapter 2.02.24. For the measurement of theFT-IR-spectra, preferably a Bruker Vector 22 spectrometer is used. FT-IRspectra are preferably base-line corrected, preferably using Bruker OPUSsoftware.

The FT-IR spectra of the anhydrates according to the invention andespecially the crystalline form A1 is given in FIG. 5.

Preferably, the anhydrates or ansolvates according to the invention andespecially the crystalline form A1 can be characterised, alternativelyor additionally, by the Raman-spectroscopy data comprising one or moreof the band positions (±2 cm⁻¹) given below, more preferably comprising9 or more of the band positions (±2 cm⁻¹) given below, even morepreferably comprising 9 or more of the band positions (±2 cm⁻¹) givenbelow, and especially comprising all the band positions (±2 cm⁻¹) givenbelow, preferably together with the relative intensities given inbrackets:

3064 cm⁻¹ (w), 2976 cm⁻¹ (m), 2934 cm⁻¹ (m), 2912 cm⁻¹ (m), 2881 cm⁻¹(m), 1603 cm⁻¹ (w), 1209 cm⁻¹ (w), 1029 cm⁻¹ (w), 1003 cm⁻¹ (m), 852cm⁻¹ (w).

More preferably, the anhydrates or ansolvates according to the inventionand especially the crystalline form A1 can be characterised,alternatively or additionally, by the Raman-spectroscopy data comprisingone or more of the band positions (±2 cm⁻¹) given below, more preferablycomprising 12 or more of the band positions (±2 cm⁻¹) given below, evenmore preferably comprising 18 or more of the band positions (±2 cm⁻¹)given below, and especially comprising all the band positions (±2 cm⁻¹)given below, preferably together with the relative intensities given inbrackets:

3064 cm⁻¹ (w), 2976 cm⁻¹ (m), 2934 cm⁻¹ (m), 2912 cm⁻¹ (m), 2881 cm⁻¹(m), 1677 cm⁻¹ (w), 1648 cm⁻¹ (w), 1603 cm⁻¹ (w), 1584 cm⁻¹ (w), 1465cm⁻¹ (w), 1407 cm⁻¹ (w), 1314 cm⁻¹ (w), 1242 cm⁻¹ (w), 1209 cm⁻¹ (w),1129 cm⁻¹ (w), 1029 cm⁻¹ (w), 1003 cm⁻¹ (m), 943 cm⁻¹ (w), 901 cm⁻¹ (w),852 cm⁻¹ (w), 623 cm⁻¹ (w), 589 cm⁻¹ (w).

The relative intensities given in brackets are preferably defined asfollows: “s”=strong (relative Raman intensity preferably ≧0.04),“m”=medium (preferably 0.04>relative Raman intensity≧0.02), “w”=weak(relative Raman intensity preferably <0.02)

The Raman or FT-Raman spectrum is preferably obtained usingAluminium-cups as sample holders for the respective solid material.

The Raman-spectroscopy data is preferably obtained byFT-Raman-spectroscopy, The Raman-spectroscopy data orFT-Raman-spectroscopy data is preferably obtained by standard techniquesas described in the European Pharmacopeia 6^(th) Edition chapter2.02.48. For the measurement of the FT-Raman-spectra, preferably aBruker RFS 100 spectrometer is used. FT-Raman spectra are preferablybase-line corrected, preferably using Bruker OPUS software.

The FT-Raman spectra of the anhydrates according to the invention andespecially the crystalline form A1 is given in FIG. 6.

Preferably, the anhydrates or ansolvates according to the invention andespecially the crystalline form A1 can be characterised, alternativelyor additionally, by dynamic vapour sorption experiments. The results canbe obtained by standard techniques as described in Rolf Hilfiker,‘Polymorphism in the Pharmaceutical Industry’, Wiley-VCH. Weinheim 2006(Chapter 9: Water Vapour Sorption, and references therein). The WaterVapour Sorption behaviour shows small water uptake levels up to 98%relative humidity (rh or r.h.), and the anhydrates or ansolvatesaccording to the invention and especially the crystalline form A1 can beclassified as non-hygroscopic acc. to Ph. Eur. criteria. No formation orconversion to a hydrate is observed. Water Vapor Sorption isotherm (25°C.) of crystallin e form A1 (SMS DVS Intrinsic) is given in FIG. 7.

The anhydrates or ansolvates according to the invention and especiallythe crystalline form A1 shows one or more properties selected from theadvantageous properties discussed above. More specifically, theanhydrates or ansolvates according to the invention and especially thecrystalline form A1 can be shown to be the thermodynamically stableansolvated form and/or thermodynamic stable form and surprisingly thethermodynamically stable form in the presence of aqueous based solvents,preferably including, but not limited to, suspensions and wettedmaterial, and especially in essentially aqueous systems, such as watersaline and the like, such as, but not limited to, suspensions and wettedmaterial, and especially in such aqueous systems in the absence ofmethanol and/or ethanol. Wetted material in this regard is preferably amixture of the respective anhydrate or ansolvate with at least 5% byweight, more preferably at least 10% by weight and especially 20% byweight, of the respective aqueous system.

More specifically, the anhydrates or ansolvates according to theinvention and especially the crystalline form A1 can shown to be thethermodynamically stable ansolvated form and/or thermodynamic stableform and surprisingly the thermodynamically stable form even in thepresence of high relative humidity.

Furthermore, the anhydrates according to the invention and especiallythe crystalline form A1 shows superior properties in terms ofhygroscopicity behaviour, with physical stability of the crystal formthroughout the entire relative humidity range (0-98%) and/or thecrystallinity and thermal behaviour are excellent.

This results in excellent properties for processing (e.g. phaseseparation by filtration, drying, milling, micronisation) and storage,thus being i.a. superior for the formulation of suspensions. Theanhydrates or ansolvates according to the invention and especially thecrystalline form A1 exhibit superior properties for the purification ofthe compound of formula I, since a reduction of structurally relatedimpurities, ionic compounds and residual solvent can be easily achieved.Thus, purificitation can be achieved in one step, where the solid forms,e.g. amorphous forms according to the conventional, prior knownprocesses, and/or other, non-anhydrate polymorhic cyrstalline formsrequire significantly higher effort for a purity in line with GMPstandards, e.g. three or more subsequent purification procedures.

The compound of formula I also forms a class of pseudopolymorphs whichincorporate different solvents in variable amounts and/or ratios,preferably ratios, and thus are solvates. These solvates arestructurally closely related as shown, e.g. by Powder X-Ray Diffractiondata, including indexing of these forms, which leads to similar unitcells. Also, selected examples for the structures will be discussedbased on single-crystal structure and structure solutions based onpowder data. Finally a discussion on the specific beneficial propertiesof this pseudopolymorphic class will be given.

Following, three preferred examples for the pseudopolymorphic forms ofthe compound according to formula I are described:

S1 (preferably also referred to as methanol-water solvate and/ormethanol solvate),S2 (preferably also referred to as ethanol-water solvate and/or ethanolsolvate), andS3 (preferably also referred to as hydrate and/or tetrahydrate). Thesepreferred examples can be further characterised as tetrasolvates.

Thus, the solid crystalline forms having a unit cell with latticeparameters ULP1 as defined before are preferably further characterisedherein as solvates and more preferably as tetrasolvates. The solvatesand/or tetrasolvates preferably include one or more crystalline formsselected from S1, S2 and S3 as defined herein, and preferably alsomixtures thereof.

The crystalline forms S1, S2 and/or S3 are preferably furthercharacterised as solvates and especially as tetrasolvates, i.e. theypreferably show an about stoichiometric amount of solvent molecules inthe respective unit cell, which is about up to 4 solvent molecules perunit cell and per molecule of the compound according to formula I.

In these solvates and more preferably in these tetrasolvates, thesolvent molecules are preferably selected from molecules of water andalcohols and more preferably selected from water, methanol and ethanol,and mixtures thereof.

Accordingly, the solvates can preferably be further characterised ashydrates, alcohol solvates (or alcoholates) or mixed water-alcoholsolvates, and more preferably as hydrates, methanol solvates (ormethanolates), ethanol solvates (or ethanolates), mixed water-methanolsolvates, mixed water-ethanol solvates or mixed water-methanol-ethanolsolvates. More specifically, if said solvates are produced from orcontacted with mixtures of solvents, e.g. recrystallised from orconditioned with mixtures of solvents, mixed solvates can be obtained.Especially preferably, mixed water alcohol solvates and especially mixedwater methanol solvates, mixed water ethanol solvates and/or mixedwater-methanol-ethanol solvates can be thus obtained. Additionally, thesolvent molecules within one solvate are partially or completelyinterchangeable for a the solvent molecules of another solvent. Thus, itis clear that the solvates, more preferably the tetrasolvates andespecially the crystalline forms S1, S2 and S3 all belong to a specificclass of solid crystalline forms.

Preferably, the tetrasolvates according to the invention, morepreferably the tetrasolvates according to the invention, more preferablythe tetrahydrates according to the invention and especially thecrystalline form S3 can be characterised, alternatively or additionally,by a melting/decomposition temperature of >210° C., more preferably217±5° C. melting/decomposition or higher, and especially 217±5° C.melting/decomposition. Preferably, the melting/decomposition temperatureobtained for the tetrasolvates according to the invention, morepreferably the tetrahydrates according to the invention and especiallyobtained for the crystalline form S3 is <250° C.

The melting/decomposition temperatures and/or thermal behaviorsdescribed herein are preferably determined by DSC (Differential Scanningcalorimetry) and TGA (ThermoGravimetric Analysis). DSC and/or TGAmethods or generally thermoanalysis methods and suitable devices fordetermining them are known in the art, for examples from EuropeanPharmacopeia 6^(th) Edition chapter 2.02.34, wherein suitable standardtechniques are described. More preferably, for the melting/decompositiontemperatures or behaviors and/or the thermoanalysis in general, aMettler Toledo DSC 821 and/or Mettler Toledo TGA 851 are used,preferably as described in the European Pharmacopeia 6^(th) Editionchapter 2.02.34.

The DSC and TGA measurements showing the thermal analysis(Mettler-Toledo DSC 821, 5 K/min, nitrogen purge gas 50 ml/min;Mettler-Toledo TGA 851, 5 K/min, nitrogen purge gas 50 ml/min) and themelting/decomposition temperature given above is shown in FIG. 23 andFIG. 24.

Preferably, the tetrasolvates according to the invention, morepreferably the tetrahydrates according to the invention and especiallythe crystalline form S3 can be characterised, alternatively oradditionally, by Powder X-Ray Diffraction and more preferably by thePowder X-Ray Diffraction pattern comprising one or more of the PowderX-ray peaks given below, more preferably comprising 3 or more of thePowder X-ray peaks given below, even more preferably 6 or more of thePowder X-ray peaks given below, and especially comprising all of the ofthe Powder X-ray peaks given below:

a) °2θ (Cu—Kα₁ Miller D ± 0.1 radiation) ± indizes No. [Å] 0.1° h k l 112.98 6.8 0 2 0 2 12.25 7.2 0 1 1 5 7.50 11.8 1 1 1 11 4.88 18.2 0 5 112 4.67 19.0 2 0 1 13 4.49 19.8 2 1 0 14 4.11 21.6 1 3 1 15 3.99 22.3 21 3or more preferably

b) °2θ (Cu—Kα₁ Miller D ± 0.1 radiation) ± indizes No. [Å] 0.1° h k l 112.98 6.8 0 2 0 2 12.25 7.2 0 1 1 5 7.50 11.8 1 1 1 11 4.88 18.3 0 5 112 4.67 19.1 2 1 0 13 4.49 19.8 2 0 1 14 4.11 21.7 1 1 3 15 3.99 22.4 23 1

Preferably, the tetrasolvates according to the invention, morepreferably the tetrahydrates according to the invention and especiallythe crystalline form S3 can be characterised, alternatively oradditionally, by Powder X-Ray Diffraction more preferably by the PowderX-Ray Diffraction pattern comprising one or more of the Powder X-raypeaks given below, more preferably comprising 9 or more of the PowderX-ray peaks given below, even more preferably 12 or more of the PowderX-ray peaks given below, and especially comprising all of the of thePowder X-ray peaks given below:

a) °2θ (Cu—Kα₁ Miller radiation) ± indizes No. D [Å] 0.1° h k l 1 12.986.8 0 2 0 2 12.25 7.2 0 1 1 3 8.91 9.9 1 0 1 4 7.83 11.3 1 1 0 5 7.5011.8 1 1 1 6 7.34 12.1 0 3 1 7 6.94 12.7 0 0 2 9 6.13 14.5 0 2 2 10 5.1517.2 1 2 2 11 4.88 18.2 0 5 1 12 4.67 19.0 2 0 1 13 4.49 19.8 2 1 0 144.11 21.6 1 3 1 15 3.99 22.3 2 1 3or more preferably

b) °2θ (Cu—Kα₁ Miller radiation) ± indizes No. D [Å] 0.1° h k l 1 12.986.8 0 2 0 2 12.25 7.2 0 1 1 3 8.91 9.9 1 1 0 4 7.83 11.3 1 0 1 5 7.5011.8 1 1 1 6 7.34 12.1 0 3 1 7 6.94 12.8 0 0 2 9 6.13 14.5 0 2 2 10 5.1517.3 1 2 2 11 4.88 18.3 0 5 1 12 4.67 19.1 2 1 0 13 4.49 19.8 2 0 1 144.11 21.7 1 1 3 15 3.99 22.4 2 3 1

Preferably, the tetrasolvates according to the invention, morepreferably the tetrahydrates according to the invention and especiallythe crystalline form S3 can be characterised, alternatively oradditionally, by Powder X-Ray Diffraction and more preferably by thePowder X-Ray Diffraction pattern comprising one or more of the PowderX-ray peaks given below, more preferably comprising 10 or more of thePowder X-ray peaks given below, even more preferably 13 or more of thePowder X-ray peaks given below, and especially comprising all of the ofthe Powder X-ray peaks given below:

a) °2θ (Cu—Kα₁ Miller D ± 0.1 radiation) ± indizes No. [Å] 0.1° h k l 112.98 6.8 0 2 0 2 12.25 7.2 0 1 1 3 8.91 9.9 1 0 1 4 7.83 11.3 1 1 0 57.50 11.8 1 1 1 6 7.34 12.1 0 3 1 7 6.94 12.7 0 0 2 8 6.50 13.6 0 4 0 96.13 14.5 0 2 2 10 5.15 17.2 1 2 2 11 4.88 18.2 0 5 1 12 4.67 19.0 2 0 113 4.49 19.8 2 1 0 14 4.11 21.6 1 3 1 15 3.99 22.3 2 1 3or more preferably

b) °2θ (Cu—Kα₁ Miller D ± 0.1 radiation) ± indizes No. [Å] 0.1° h k l 112.98 6.8 0 2 0 2 12.25 7.2 0 1 1 3 8.91 9.9 1 1 0 4 7.83 11.3 1 0 1 57.50 11.8 1 1 1 6 7.34 12.1 0 3 1 7 6.94 12.8 0 0 2 8 6.50 13.7 0 4 0 96.13 14.5 0 2 2 10 5.15 17.3 1 2 2 11 4.88 18.3 0 5 1 12 4.67 19.1 2 1 013 4.49 19.8 2 0 1 14 4.11 21.7 1 1 3 15 3.99 22.4 2 3 1

FIG. 25 shows the Powder X-ray diffractogram of crystalline form S3

The Powder X-Ray Diffraction and more preferably the Powder X-RayDiffraction pattern is preferably performed or determined as describedherein and especially performed or determined by standard techniques asdescribed in the European Pharmacopeia 6^(th) Edition chapter 2.9.33,and is even more preferably obtained with the parameters Cu—Kα₁radiation and/or λ=1.5406 Å, preferably on a Stoe StadiP 611 KLdiffractometer.

Preferably, the tetrasolvates according to the invention, morepreferably the tetrahydrates according to the invention and especiallythe crystalline form S3 can be characterised, alternatively oradditionally, by Single Crystal X-Ray Structure Data, for example SingleCrystal X-Ray Structure Data obtained on a diffractometer preferablyequipped with a graphite monochromator and CCD Detector, preferablyusing Mo K_(α) radiation, preferably at a temperature of 298 K±5 K, andeven more preferably on a XCalibur diffractometer from OxfordDiffraction equipped with graphite monochromator and CCD Detector usingMo K_(α) radiation at about 298 K.

According to the Single Crystal X-Ray Structure Data obtained, thetetrahydrates of the compound of formula I according to the inventionand especially the crystalline form S3 crystallises in the orthorhombicspace group P 2₁ 2₁ 2₁ with the lattice parameters a=9.6 Å, b=25.9 Å,c=13.9 Å (±0.1 Å) and the unit cell volume is preferably is 3396 (±10)Å³

From the single crystal structure it is obvious that form S3 representsa tetrasolvate and more specifically a tetrahydrate.

The Single Crystal X-Ray Structure is depicted in FIG. 26. Additionalstructural Information based on said Single Crystal X-Ray Structure datais given in FIGS. 26 a, 26 b and 26 c.

Preferably, the tetrasolvates according to the invention, morepreferably the tetrahydrates according to the invention and especiallythe crystalline form S3 can be characterised, alternatively oradditionally, by the infrared-spectroscopy data comprising one or moreof the

band positions (±2 cm⁻¹) given below, more preferably comprising 3 ormore of the band positions (±2 cm⁻¹) given below, even more preferablycomprising 6 or more of the band positions (±2 cm⁻¹) given below, andespecially comprising all the band positions (±2 cm⁻¹) given below,preferably together with the relative intensities given in brackets:

3319 cm⁻¹ (s), 3067 cm⁻¹ (s), 2966 cm⁻¹ (s), 1668 cm⁻¹ (s), 1541 cm⁻¹(s), 1395 cm⁻¹ (s), 704 cm⁻¹ (m)

More preferably, the tetrasolvates according to the invention, morepreferably the tetrahydrates according to the invention and especiallythe crystalline form S3 can be characterised, alternatively oradditionally, by the infrared-spectroscopy data comprising one or moreof the band positions (±2 cm⁻¹) given below, more preferably comprising6 or more of the band positions (±2 cm⁻¹) given below, even morepreferably comprising 9 or more of the band positions (±2 cm⁻¹) givenbelow, and especially comprising all the band positions (±2 cm⁻¹) givenbelow, preferably together with the relative intensities given inbrackets:

3428 cm⁻¹ (s), 3319 cm⁻¹ (s), 3067 cm⁻¹ (s), 2966 cm⁻¹ (s), 2874 cm⁻¹(m), 1668 cm⁻¹ (s), 1541 cm⁻¹ (s), 1455 cm⁻¹ (s), 1395 cm⁻¹ (s), 1232cm⁻¹ (m), 704 cm⁻¹ (m)

The relative intensities given in brackets are preferably defined asfollows: *“s”=strong (transmittance preferably ≦50%), “m”=medium(preferably 50%<transmittance≦70%), “w”=weak (transmittance preferably>70%)

The IR or FT-IR spectrum is preferably obtained using a KBr pellet assample preparation technique.

The IR-spectroscopy data is preferably obtained by FT-IR-spectroscopy,The IR-spectroscopy data or FT-IR-spectroscopy data is preferablyobtained by standard techniques as described in the EuropeanPharmacopeia 6^(th) Edition chapter 2.02.24. For the measurement of theFT-IR-spectra, preferably a Bruker Vector 22 spectrometer is used. FT-IRspectra are preferably base-line corrected, preferably using Bruker OPUSsoftware.

The FT-IR spectra of the tetrasolvates according to the invention, morepreferably the tetrahydrates according to the invention and especiallythe crystalline form S3 is given in FIG. 27.

Preferably, the tetrasolvates according to the invention, morepreferably the tetrahydrates according to the invention and especiallythe crystalline form S3 can be characterised, alternatively oradditionally, by the Raman-spectroscopy data comprising one or more ofthe

band positions (±2 cm⁻¹) given below, more preferably comprising 4 ormore of the band positions (±2 cm⁻¹) given below, even more preferablycomprising 7 or more of the band positions (±2 cm⁻¹) given below, andespecially comprising all the band positions (±2 cm⁻¹) given below,preferably together with the relative intensities given in brackets:

3069 cm⁻¹ (m), 2931 cm⁻¹ (s), 1666 cm⁻¹ (m), 1607 cm⁻¹ (w), 1443 cm⁻¹(w), 1339 cm⁻¹ (w), 1205 cm⁻¹ (w), 1004 cm⁻¹ (s), 911 cm⁻¹ (m).

More preferably, the tetrasolvates according to the invention, morepreferably the tetrahydrates according to the invention and especiallythe crystalline form S3 can be characterised, alternatively oradditionally, by the Raman-spectroscopy data comprising one or more ofthe and positions (±2 cm⁻¹) given below, more preferably comprising 9 ormore of the band positions (±2 cm⁻¹) given below, even more preferablycomprising 12 or more of the band positions (±2 cm⁻¹) given below, andespecially comprising all the band positions (±2 cm⁻¹) given below,preferably together with the relative intensities given in brackets:

3069 cm⁻¹ (m), 2931 cm⁻¹ (s), 1666 cm⁻¹ (m), 1607 cm⁻¹ (w), 1585 cm⁻¹(w), 1443 cm⁻¹ (w), 1339 cm⁻¹ (w), 1205 cm⁻¹ (w), 1122 cm⁻¹ (w), 1033cm⁻¹ (w), 1004 cm⁻¹ (s), 936 cm⁻¹ (w), 911 cm⁻¹ (m), 825 cm⁻¹ (w), 624cm⁻¹ (w), 519 cm⁻¹ (w),

The relative intensities given in brackets are preferably defined asfollows: “s”=strong (relative Raman intensity preferably ≧0.04),“m”=medium (preferably 0.04>relative Raman intensity≧0.02), “w”=weak(relative Raman intensity preferably <0.02)

The Raman or FT-Raman spectrum is preferably obtained usingAluminium-cups as sample holders for the respective solid material.

The Raman-spectroscopy data is preferably obtained byFT-Raman-spectroscopy, The Raman-spectroscopy data orFT-Raman-spectroscopy data is preferably obtained by standard techniquesas described in the European Pharmacopeia 6^(th) Edition chapter 2.02.24and/or 2.02.48. For the measurement of the FT-Raman-spectra, preferablya Bruker RFS 100 spectrometer is used. FT-Raman spectra are preferablybase-line corrected, preferably using Bruker OPUS software.

The FT-Raman spectra of the tetrasolvates according to the invention andespecially the crystalline form S3 is given in FIG. 28.

Preferably, the tetrasolvates according to the invention, morepreferably the tetrahydrates according to the invention and especiallythe crystalline form S3 can be characterised, alternatively oradditionally, by dynamic vapour sorption experiments. The results can beobtained by standard techniques as described in Rolf Hilfiker,‘Polymorphism in the Pharmaceutical Industry’, Wiley-VCH. Weinheim 2006(Chapter 9: Water Vapour Sorption, and references therein).

The Water Vapour Sorption behaviour shows a loss of water molecules (ca.9% by weight) within the initial drying step (0% relative humidity(rh)). During the water adsorption cycle an assembly of water moleculesin the lattice can be shown (ca. 10% by weight) at elevated rh. In thesecond desorption cycle, a loss of this amount of water can be shown.The Water Vapour Sorption isotherm (25° C.) of form S3 is shown in FIG.29.

Overall, the thermal analysis data given herein confirms thetetrahydrate structure, with complete dehydration observed at elevatedtemperature (for the tetrahydrate the calculated water content is 10.9wt %) in the TGA. Water vapour sorption data show that even under dryconditions (0% rh) at 25° C., only ˜9 wt % water are split-off, showingthat preferably no complete dehydration of the structure occurs. Watervapour sorption isotherm (25° C.) of crystalline form S3 (SMS DVSIntrinsic) is given in FIG. 29.

Surprisingly, it has been found that the water molecules within thehydrates according to the invention and especially the water moleculeswithin the tetrahydrates according to the invention can be substituted,partially or totally, by alcohol molecules, preferably by alcoholmolecules selected from the group consisting of monools, diols or triolshaving 1 to 6 carbon atoms, more preferably monools having 1 to 4 carbonatoms and especially monools selected from the group consisting ofmethanol and ethanol, and mixtures thereof.

Experimental methods, such as dynamic vapour sorption/desorptionexperiments, single crystal X-Ray experiments and/or powder x-rayexperiments show that starting e.g. from the tetrahydrate characterizedas crystalline form S3, the water molecules of said tetrahydrate can bepartly and/or about totally removed from said tetrahydrate and/or besubstituted by methanol and/or ethanol.

For example, dynamic vapour sorption/desorption experiments, preferablyusing vapours of organic solvents and/or water, preferably vapours oforganic solvents selected from one or more alcohols preferably alcoholsas defined herein, and/or water and especially vapours of methanol,ethanol and/water, show that the water molecules from said tetrahydratecan continuously be substituted by alcohol molecules and especiallymethanol and/or ethanol molecules, potentially until a tetra alcoholsolvate or a mixed alcohol-water solvate or tetrasolvate is formed.

As another example, conditioning of

a) amorphous material of the compound according to formula I orb) hydrate formsunder mixed water-alcohol atmospheres—preferably water-ethanolatmospheres—representing different water and alcohol partial pressuresyielded in both cases crystalline solvates exhibiting differentstoichiometries with up to 4 molecules of water or up to 2 molecules ofethanol per molecule of the compound according to formula I, e.g. thetetrahydrate S3 (4 molecules of water) or the diethanolate S2 (2Molecules of ethanol, see e.g. FIG. 31)), depending on the respectiveconditions used. Stoichiometries as determined by Karl-Fischer titrationfor quantification of water and HS-GC for quantification of ethanol aredepicted in FIG. 30. In the diagram also points representingstochiometries with more than 4 molecules of water per molecule of thecompound according to formula I are depicted. As there is no space formore than 4 molecules of water in the crystal lattice of thetetrahydrates, excess amounts of more than 4 molecules of waterrepresent adsorbed moisture.

The results (see also Example 13) show that there is a floatingtransition from the hydrate form S3 into the mixed water-ethanol orwaterless ethanol solvate form S2 with increasing ethanol vapourpressure. All solvates (including the hydrates) have similar latticeparameters, which only slightly increase with the assembly of ethanolmolecules

As still another example, conditioning of amorphous material of thecompound according to formula I or hydrate forms under methanolatmosphere yielded crystalline solvates with 2 molecules methanol permolecule of the compound according to formula I.

Thus, crystalline forms that can be characterised as tetrasolvates areobtainable, which have a solvent content between up to approximately100% of water (referring to 4 molecules of water per molecule of thecompound according to formula I, i.e. referring a tetrahydrate) and asolvent content of up to approximately 100% of alcohol (referring to 4molecules of alcohol per molecule of the compound according to formulaI, i.e. referring a tetraalcoholate) and preferably the intermediates inbetween.

The results are further discussed above and/or below and especiallydiscussed in the Tables 1 and 2 given below. For example, metastablecrystalline solvates being mixed Dihydrate-dialcoholates (referring to 2molecules of water and 2 molecules of alcohol per molecule of thecompound according to formula I), later in detail characterized asDihydrate-dimethanolate and crystalline form S1 and asDihydrate-diethanolate and crystalline form S2, respectively, can beobtained and are discussed in detail above and/or below. Thesestoichiometries were derived and/or extrapolated from the hereindescribed Dynamic Vapor Sorption experiments. New X-ray experimentsprove that metastable crystalline solvates also can be present as mixedDihydrate-alcoholates or more specifically Dihydrate-monoalcoholates(referring to 2 molecules of water and 1 molecule of alcohol permolecule of the compound according to formula I) as furthermanifestations of these non-stoichiometric class of pseudopolymorphs,later in detail characterized as Dihydrate-methanolate,Dihydrate-monomethanolate and/or another manifestation of crystallineform S1, and as Dihydrate-ethanolate, Dihydrate-monoethanolate and/oranother manifestation of crystalline form S2, respectively, can beobtained and are discussed in detail above and/or below.

Special reference in this regard is given to the Tables 1 and 2 givenbelow and the paragraphs relating thereto.

The following tables show the respective calculated gravimetric waterand/or methanol contents for tetrasolvates ranging from tetrahydrate totetraalcoholate; in this calculation, integer steps in the solvatestoichiometry have been used based on one molecule of the compoundaccording to formula I, and in total four molecules of the respectivesolvent or solvent mixture in said tetrasolvates. This can preferably beexpressed by the following formulae:

[cyclo-(Arg-Gly-Asp-DPhe-NMe-Val)].[Alcohol]_(X).[H₂O]_((y)) (with 0≦x≦4and 0≦y≦4),more specifically:[cyclo-(Arg-Gly-Asp-DPhe-NMe-Val)].[Alcohol]_(x).[H₂O]_((4-x)) with0≦x≦4) (for the interconversion between the tetrahydrates and thetetraalcoholates)or[cyclo-(Arg-Gly-Asp-DPhe-NMe-Val)].[Alcohol]_(x).[H₂O]_((y)) with 0≦y≦4and x≦2−0.5*y and x≦1) (for the interconversion between thetetrahydrates and the Dihydrate-alcoholates or more specificallyDihydrate-monoalcoholates). (“*”=multiplication sign)

TABLE 1 (water/methanol exchange) molar mass of Methanol Watergravimetric gravimetric solvate equiva- equiva- molar methanol waterrelative to lents lents mass content content tetrahydrate [x] [y][g/mol] [%] [%] [%] 0 4 660.75 0.0 10.9 100.0% 1 3 674.77 4.7 8.0 102.1%2 2 688.79 9.3 5.2 104.2% 3 1 702.81 13.7 2.6 106.4% 4 0 716.83 17.9 0.0108.5% 1 2 656.75 4.9 5.5 99.4 2 0 652.75 9.8 0.0 98.8

TABLE 2 (water/ethanol exchange) molar mass of Ethanol Water gravimetricgravimetric solvate equiva- equiva- molar ethanol water relative tolents lents mass content content tetrahydrate [x] [y [g/mol] [%] [%] [%]0 4 660.75 0.0 10.9 100.0 1 3 688.80 6.7 7.8 104.3 2 2 716.85 12.9 5.0108.5 3 1 744.90 18.6 2.4 112.7 4 0 772.95 23.8 0.0 117.0 1 2 670.78 6.95.4 101.5 2 0 680.81 13.5 0.0 103.0

In the respective dynamic vapor sorption experiments discussed in moredetail herein using methanol vapor at 98% relative saturation for theDihydrate-dimethanolate/crystalline form S1 at 25° C. starting with thetetrahydrate a mass gain of 9% has been obtained. This is in goodagreement with the above shown results for the tetramethanolate(calculated 108.5%, i.e. 8.5% of mass gain).

In the respective dynamic vapor sorption experiments discussed in moredetail herein using ethanol vapor at 98% relative saturation for theDihydrate-diethanolate/crystalline form S2 at 25° C. starting with thetetrahydrate a mass gain of 17% has been obtained. This is in goodagreement with the above shown results for the tetraethanolate(calculated 117.0%, i.e. 17.0% of mass gain).

As is shown above and/or below, the tetrasolvates according to theinvention are preferably convertible, more preferably convertiblebetween essentially pure tetrahydrates and essentially puretetraalcoholates, and potentially all intermediates in between, andpreferably the desolvates thereof (exhibiting lower water and/or alcoholcontent), preferably exemplified by:

the mixed Dihydrate-dialcoholates which are discussed in detail aboveand/or below, and

the Dihydrate-alcoholates or Dihydrate-monoalcoholates (as described bythe formula [cyclo-(Arg-Gly-Asp-DPhe-NMe-Val)].[Alcohol]_(x).[H₂O]_((y))with 0≦y≦4 and x≦2−0.5·y and x≦1), and more specifically S1 and/or S2.

Since those tetrasolvates have very similar structural features, e.g.the crystallographic parameters, the analytical data and/or physicalproperties and additionally are convertible, it is clear that thetetrasolvates form a class or subclass of the crystalline formsaccording to the invention and/or of the solid materials according tothe invention.

Accordingly, the tetrasolvates are a preferred subject of the instantinvention are according to the invention, preferably the tetrasolvatesas characterised herein.

For reasons of clarity, tetrasolvates that contain three or moreequivalents of water (i.e. have a water content of >75 mole %, based onthe total amount of solvent contained in the respective crystallineform) and contain less than one equivalent of one or more solvents otherthan water, preferably less than one equivalent of one or more alcohols,preferably selected from methanol and ethanol, are preferably referredto as hydrates, hydrates according to the invention orhydrate-tetrasolvates.

For reasons of clarity, tetrasolvates that contain close to fourequivalents of water (i.e. have a water content of >90 mole % andpreferably of >95 mole %, based on the total amount of solvent containedin the respective crystalline form) are preferably referred to astetrahydrates or tetrahydrates according to the invention.

For reasons of clarity, tetrasolvates that contain one or moreequivalents of alcohol (i.e. have an alcohol content of 25 mole % orhigher, based on the total amount of solvent contained in the respectivecrystalline form) are preferably referred to as alcoholates, alcoholatesaccording to the invention or alcoholate-tetrasolvates. Examples of suchalcoholates or alcoholate-tetrasolvates are the methanolate and/orethanolate (or methanolate-tetrasolvate and/or ethanolate-tetrasolvate)according to the invention.

For reasons of clarity, tetrasolvates that contain close to fourequivalents of one or more alcohols (i.e. have an total alcohol contentof >90 mole % and preferably of >95 mole %, based on the total amount ofsolvent contained in the respective crystalline form) are preferablyreferred to as tetraalcoholates or tetraalcoholates according to theinvention. Examples of such tetraalcoholates are the tetramethanolateand/or tetraethanolate or the tetramethanolate and/or tetraethanolateaccording to the invention.

Two more tetrasolvates that can be described as alcohol solvates,alcoholate-tetrasolvates or desolvates thereof or more preferablydescribed as Dihydrate-dialcoholates, Dihydrate-alcoholates orDihydrate-monoalcoholates are described below:

Preferably, the tetrasolvates according to the invention, morepreferably the Dihydrate-dimethanolate, the Dihydrate-methanolate, theDihydrate-monoethanolate, the Dimethanolate and/or the desolvatesthereof and especially the crystalline form S1 can be characterised,alternatively or additionally, by a melting/decomposition temperatureof >205° C., more preferably 210±5° C. melting/decomposition ° C. orhigher, and especially 210±5° C. melting/decomposition. Preferably, saidmelting/decomposition temperature obtained for the tetrasolvatesaccording to the invention, more preferably obtained for theDihydrate-dimethanolate, the Dihydrate-methanolate, theDihydrate-monoethanolate, the Dimethanolate and/or the desolvatesthereof and especially obtained for the crystalline form S1 is <250° C.

The melting/decomposition temperatures and/or thermal behaviorsdescribed herein are preferably determined by DSC (Differential ScanningCalorimetry) and TGA (ThermoGravimetric Analysis). DSC and/or TGAmethods or generally thermoanalytic methods and suitable devices fordetermining them are known in the art, for examples from EuropeanPharmacopeia 6^(th) Edition chapter 2.02.34, wherein suitable standardtechniques are described. More preferably, for the melting/decompositiontemperatures or behaviors and/or the thermoanalysis in general, aMettler Toledo DSC 821 and/or Mettler Toledo TGA 851 are used,preferably as described in the European Pharmacopeia 6^(th) Editionchapter 2.02.34.

The DSC and TGA measurements showing the thermal analysis(Mettler-Toledo DSC 821, 5 K/min, nitrogen purge gas 50 ml/min;Mettler-Toledo TGA 851, 5 K/min, nitrogen purge gas 50 ml/min) and themelting/decomposition temperature given above is shown in FIG. 8 andFIG. 9.

Preferably, the tetrasolvates according to the invention, morepreferably the Dihydrate-dimethanolate, the Dihydrate-methanolate, theDihydrate-monoethanolate, the Dimethanolate and/or the desolvatesthereof, and especially the crystalline form S1 can be characterised,alternatively or additionally, by Powder X-Ray Diffraction and morepreferably by the Powder X-Ray Diffraction pattern comprising one ormore of the Powder X-ray peaks given below, more preferably comprising 6or more of the Powder X-ray peaks given below, even more preferably 9 ormore of the Powder X-ray peaks given below, and especially comprisingall of the of the Powder X-ray peaks given below:

Miller D ± 0.1 °2θ (Co—Kα₁ indizes No. [Å] radiation) ± 0.1° h k l 113.05 7.9 0 2 0 2 12.47 8.3 0 1 1 5 7.88 13.1 1 0 −1 7 7.60 13.6 1 1 −18 7.41 13.9 0 3 1 9 7.09 14.5 0 0 2 10 6.51 15.8 0 4 0 11 6.23 16.5 0 22 12 5.92 17.4 0 4 1 13 4.89 21.1 0 5 1 14 4.80 21.5 0 4 2

Preferably, the tetrasolvates according to the invention, morepreferably the Dihydrate-dimethanolate, the Dihydrate-methanolate, theDihydrate-monoethanolate, the Dimethanolate and/or the desolvatesthereof, and especially the crystalline form S1 can be characterised,alternatively or additionally, by Powder X-Ray Diffraction morepreferably by the Powder X-Ray Diffraction pattern comprising one ormore of the Powder X-ray peaks given below, more preferably comprising 8or more of the Powder X-ray peaks given below, even more preferably 12or more of the Powder X-ray peaks given below, and especially comprisingall of the of the Powder X-ray peaks given below:

Miller °2θ (Co—Kα₁ indizes No. D [Å] radiation) ± 0.1° h k l 0 14.20 7.30 0 1 1 13.05 7.9 0 2 0 2 12.47 8.3 0 1 1 3 9.62 10.7 0 2 1 4 8.81 11.71 1 0 5 7.88 13.1 1 0 −1 6 7.74 13.3 1 0 1 7 7.60 13.6 1 1 −1 8 7.4113.9 0 3 1 9 7.09 14.5 0 0 2 10 6.51 15.8 0 4 0 11 6.23 16.5 0 2 2 125.92 17.4 0 4 1 13 4.89 21.1 0 5 1 14 4.80 21.5 0 4 2

Preferably, the up tp tetrasolvates according to the invention, morepreferably the Dihydrate-dimethanolate, the Dihydrate-methanolate, theDihydrate-monoethanolate, the Dimethanolate and/or the desolvatesthereof, and especially the crystalline form S1 can be characterised,alternatively or additionally, by Powder X-Ray Diffraction and morepreferably by the Powder X-Ray Diffraction pattern comprising one ormore of the Powder X-ray peaks given below, more preferably comprising10 or more of the Powder X-ray peaks given below, even more preferably12 or more of the Powder X-ray peaks given below, and especiallycomprising all of the of the Powder X-ray peaks given below:

Miller D ± 0.1 °2θ (Co—Kα₁ indizes No. [Å] radiation) ± 0.1° h k l 014.20 7.3 0 0 1 1 13.05 7.9 0 2 0 2 12.47 8.3 0 1 1 3 9.62 10.7 0 2 1 48.81 11.7 1 1 0 5 7.88 13.1 1 0 −1 6 7.74 13.3 1 0 1 7 7.60 13.6 1 1 −18 7.41 13.9 0 3 1 9 7.09 14.5 0 0 2 10 6.51 15.8 0 4 0 11 6.23 16.5 0 22 12 5.92 17.4 0 4 1 13 4.89 21.1 0 5 1 14 4.80 21.5 0 4 2

The Powder X-ray diffractogram of crystalline form S1 is shown in FIG.10

The PXRD pattern can be successfully indexed with the followingmonoclinic unit cell (space group P21):

a=9.4 Å, b=25.9 Å, c=14.1 Å (±0.1 Å), β=91.2° (±0.1), V˜3430 (±10) Å³

The Powder X-Ray Diffraction and more preferably the Powder X-RayDiffraction pattern is preferably performed or determined as describedherein and especially performed or determined by standard techniques asdescribed in the European Pharmacopeia 6^(th) Edition chapter 2.9.33,and is even more preferably obtained with the parameters Cu—Kα₁radiation and/or λ=1.5406 Å, preferably on a Stoe StadiP 611 KLdiffractometer.

Preferably, the tetrasolvates according to the invention, morepreferably the Dihydrate-dimethanolate, the Dihydrate-methanolate, theDihydrate-monoethanolate, the Dimethanolate and/or the desolvatesthereof, and especially the crystalline form S1 can be characterised,alternatively or additionally, by Single Crystal X-Ray Structure Data,for example Single Crystal X-Ray Structure Data obtained on adiffractometer preferably equipped with a graphite monochromator and CCDDetector, preferably using Mo K_(α) radiation, preferably at atemperature of 298 K±5 K, and even more preferably on a XCaliburdiffractometer from Oxford Diffraction equipped with graphitemonochromator and CCD Detector using Mo K_(α) radiation at about 298 K.

Preferably, the tetrasolvates according to the invention, morepreferably the Dihydrate-dimethanolate, the Dihydrate-methanolate, theDihydrate-monoethanolate, the Dimethanolate and/or the desolvatesthereof, and especially the crystalline form S1 can be characterised,alternatively or additionally, by the infrared-spectroscopy datacomprising one or more of the band positions (±2 cm⁻¹) given below, morepreferably comprising 3 or more of the band positions (±2 cm⁻¹) givenbelow, even more preferably comprising 6 or more of the band positions(±2 cm⁻¹) given below, and especially comprising all the band positions(±2 cm⁻¹) given below, preferably together with the relative intensitiesgiven in brackets:

3311 cm⁻¹ (s), 2965 cm⁻¹ (m), 2875 cm⁻¹ (w), 1668 cm⁻¹ (s), 1542 cm⁻¹(s), 1396 cm⁻¹ (m), 1028 cm⁻¹ (w), 707 cm⁻¹ (m)

More preferably, the tetrasolvates according to the invention, morepreferably the Dihydrate-dimethanolate, the Dihydrate-methanolate, theDihydrate-monoethanolate, the Dimethanolate and/or the desolvatesthereof, and especially the crystalline form S1 can be characterised,alternatively or additionally, by the infrared-spectroscopy datacomprising one or more of the band positions (±2 cm⁻¹) given below, morepreferably comprising 6 or more of the band positions (±2 cm⁻¹) givenbelow, even more preferably comprising 9 or more of the band positions(±2 cm⁻¹) given below, and especially comprising all the band positions(±2 cm⁻¹) given below, preferably together with the relative intensitiesgiven in brackets:

3311 cm⁻¹ (s), 3067 cm⁻¹ (m), 2965 cm⁻¹ (m), 2937 cm⁻¹ (m), 2875 cm⁻¹(w), 1668 cm⁻¹ (s), 1542 cm⁻¹ (s), 1456 cm⁻¹ (m), 1396 cm⁻¹ (m), 1028cm⁻¹ (w), 707 cm⁻¹ (m)

The relative intensities given in brackets are preferably defined asfollows: *“s”=strong (transmittance preferably ≦50%), “m”=medium(preferably 50%<transmittance≦70%), “w”=weak (transmittance preferably>70%)

The IR or FT-IR spectrum is preferably obtained using a KBr pellet assample preparation technique.

The IR-spectroscopy data is preferably obtained by FT-IR-spectroscopy,The IR-spectroscopy data or FT-IR-spectroscopy data is preferablyobtained by standard techniques as described in the EuropeanPharmacopeia 6^(th) Edition chapter 2.02.24. For the measurement of theFT-IR-spectra, preferably a Bruker Vector 22 spectrometer is used. FT-IRspectra are preferably base-line corrected, preferably using Bruker OPUSsoftware.

The FT-IR spectra of the tetrasolvates according to the invention, morepreferably the Dihydrate-dimethanolate, the Dihydrate-methanolate, theDihydrate-monoethanolate, the Dimethanolate and/or the desolvatesthereof, and especially the crystalline form S1 is given in FIG. 11.

Preferably, the tetrasolvates according to the invention, morepreferably the Dihydrate-dimethanolate, the Dihydrate-methanolate, theDihydrate-monoethanolate, the Dimethanolate and/or the desolvatesthereof, and especially the crystalline form S1 can be characterised,alternatively or additionally, by the Raman-spectroscopy data comprisingone or more of the band positions (±2 cm⁻¹) given below, more preferablycomprising 5 or more of the band positions (±2 cm⁻¹) given below, evenmore preferably comprising 8 or more of the band positions (±2 cm⁻¹)given below, and especially comprising all the band positions (±2 cm⁻¹)given below, preferably together with the relative intensities given inbrackets:

3067 cm⁻¹ (w), 2936 cm⁻¹ (s), 1668 cm⁻¹ (m), 1606 cm⁻¹ (w), 1446 cm⁻¹(w), 1338 cm⁻¹ (w), 1203 cm⁻¹ (w), 1033 cm⁻¹ (w), 1004 cm⁻¹ (s), 904cm⁻¹ (m), 624 cm⁻¹ (w).

More preferably, the tetrasolvates according to the invention, morepreferably the Dihydrate-dimethanolate, the Dihydrate-methanolate, theDihydrate-monoethanolate, the Dimethanolate and/or the desolvatesthereof, and especially the crystalline form S1 can be characterised,alternatively or additionally, by the Raman-spectroscopy data comprisingone or more of the and positions (±2 cm⁻¹) given below, more preferablycomprising 9 or more of the band positions (±2 cm⁻¹) given below, evenmore preferably comprising 12 or more of the band positions (±2 cm⁻¹)given below, and especially comprising all the band positions (±2 cm⁻¹)given below, preferably together with the relative intensities given inbrackets:

3067 cm⁻¹ (w), 2936 cm⁻¹ (s), 1668 cm⁻¹ (m), 1606 cm⁻¹ (w), 1585 cm⁻¹(w), 1446 cm⁻¹ (w), 1338 cm⁻¹ (w), 1203 cm⁻¹ (w), 1123 cm⁻¹ (w), 1033cm⁻¹ (w), 1004 cm⁻¹ (s), 904 cm⁻¹ (m), 824 cm⁻¹ (w), 624 cm⁻¹ (w), 523cm⁻¹ (w).

The relative intensities given in brackets are preferably defined asfollows: “s”=strong (relative Raman intensity preferably ≧0.04),“m”=medium (preferably 0.04>relative Raman intensity≧0.02), “w”=weak(relative Raman intensity preferably <0.02)

The Raman or FT-Raman spectrum is preferably obtained usingAluminium-cups as sample holders for the respective solid material.

The Raman-spectroscopy data is preferably obtained byFT-Raman-spectroscopy, The Raman-spectroscopy data orFT-Raman-spectroscopy data is preferably obtained by standard techniquesas described in the European Pharmacopeia 6^(th) Edition chapter2.02.48. For the measurement of the FT-Raman-spectra, preferably aBruker RFS 100 spectrometer is used. FT-Raman spectra are preferablybase-line corrected, preferably using Bruker OPUS software.

The FT-Raman spectra of the tetrasolvates according to the invention andespecially the crystalline form S1 is given in FIG. 12.

Preferably, the tetrasolvates according to the invention, morepreferably the Dihydrate-dimethanolate, the Dihydrate-methanolate, theDihydrate-monoethanolate, the Dimethanolate and/or the desolvatesthereof, and especially the crystalline form S1 can be characterised,alternatively or additionally, by dynamic vapour experiments using watervapour and/or methanol vapour. The results can be obtained by standardtechniques as described in Rolf Hilfiker, ‘Polymorphism in thePharmaceutical Industry’, Wiley-VCH. Weinheim 2006 (Chapter 9: WaterVapour Sorption, and references therein).

The Water Vapour Sorption behaviour of the tetrasolvates according tothe invention, more preferably the Dihydrate-dimethanolate, theDihydrate-methanolate, the Dihydrate-monoethanolate, the Dimethanolateand/or the desolvates thereof, and especially the crystalline form S1shows a mass loss of approx. 8 wt % in the first desorption cycle (whichis slightly lower than the observed Methanol mass gain in the MethanolVapour Sorption experiment). Upon water vapour adsorption, an assemblyof water molecules in the lattice is observed, with a maximum weightgain of approx. 8 wt % at elevated rh. In the second desorption cycle atotal mass loss of approx. 9.9 wt % is observed. For a DihydrateDi-Methanolate of the compound of formula I, the calculated Methanolcontent equals 9.3 wt %. Form S1 can be shown to be thethermodynamically stable form in an atmosphere of 100% Methanol vapour.Water Vapor Sorption isotherm (25° C.) of crystalline form S1 (SMS DVSIntrinsic) is given in FIG. 13. Methanol Vapour Sorption Isotherm (25°C.) of a hydrate form to form S1 (SMS DVS Advantage) FIG. 14.

Thus, crystalline form S1 is a crystalline Methanol solvate form or amixed water/methanol solvate form, preferably selected from theDihydrate-methanolate, the Dihydrate-monoethanolate, the Dimethanolateand/or the desolvates thereof, which can be obtained e.g. via MethanolVapour Sorption, preferably via Methanol Vapour Sorption starting with ahydrate structure, such as the hydrates according to the invention andespecially the tetrahydrate according to the invention, i.e crystallineform S3. From the Methanol Vapour Sorption curve as shown in FIG. 13 andas discussed above, it can be seen that at elevated Methanol partialpressure, approx. 9 wt % Methanol are taken up by the sample.

Preferably, the tetrasolvates according to the invention, morepreferably the Dihydrate-diethanolate, the Dihydrate-ethanolate, theDihydrate-monoethanolate, the Diethanolate and/or the desolvatesthereof, and especially the crystalline form S2 can be characterised,alternatively or additionally, by a melting/decomposition temperatureof >205° C., more preferably 210±5° C. melting/decomposition ° C. orhigher, and especially 210±5° C. melting/decomposition. Preferably, saidmelting/decomposition temperature obtained for the tetrasolvatesaccording to the invention, more preferably the Dihydrate-diethanolate,the Dihydrate-ethanolate, the Dihydrate-monoethanolate, the Diethanolateand/or the desolvates thereof, and especially obtained for thecrystalline form S2 is <250° C.

The melting/decomposition temperatures and/or thermal behaviorsdescribed herein are preferably determined by DSC (Differential ScanningCalorimetry) and TGA (ThermoGravimetric Analysis). DSC and/or TGAmethods or generally thermoanalysis methods and suitable devices fordetermining them are known in the art, for examples from EuropeanPharmacopeia 6^(th) Edition chapter 2.02.34, wherein suitable standardtechniques are described. More preferably, for the melting/decompositiontemperatures or behaviors and/or the thermoanalysis in general, aMettler Toledo DSC 821 and/or Mettler Toledo TGA 851 are used,preferably as described in the European Pharmacopeia 6^(th) Editionchapter 2.02.34.

The DSC and TGA measurements showing the thermal analysis(Mettler-Toledo DSC 821, 5 K/min, nitrogen purge gas 50 ml/min;Mettler-Toledo TGA 851, 5 K/min, nitrogen purge gas 50 ml/min) and themelting/decomposition temperature given above is shown in FIG. 15 andFIG. 16.

Preferably, the tetrasolvates according to the invention, morepreferably the Dihydrate-diethanolate, the Dihydrate-ethanolate, theDihydrate-monoethanolate, the Diethanolate and/or the desolvatesthereof, and especially the crystalline form S2 can be characterised,alternatively or additionally, by Powder X-Ray Diffraction and morepreferably by the Powder X-Ray Diffraction pattern comprising one ormore of the Powder X-ray peaks given below, more preferably comprising 3or more of the Powder X-ray peaks given below, even more preferably 5 ormore of the Powder X-ray peaks given below, and especially comprisingall of the of the Powder X-ray peaks given below:

a) Miller D ± 0.1 °2θ (Co—Kα₁ indizes No. [Å] radiation) ± 0.1° h k l 113.32 7.7 2 0 0 2 12.89 8.0 1 1 0 4 7.87 13.1 0 1 1 5 7.54 13.6 1 1 1 67.36 14.0 0 2 0 9 4.82 21.3 1 3 0 10 4.58 22.5 1 0 2or more preferably

b) Miller D ± 0.1 °2θ (Cu—Kα₁ indizes No. [Å] radiation) ± 0.1° k l hl 113.32 7.7 2 0 0 2 12.89 8.0 1 1 0 4 7.87 13.1 0 1 1 5 7.54 13.6 1 1 1 67.36 14.0 0 2 0 9 4.82 21.3 3 2 1 10 4.58 22.5 1 0 2

Preferably, the tetrasolvates according to the invention, morepreferably the Dihydrate-diethanolate, the Dihydrate-ethanolate, theDihydrate-monoethanolate, the Diethanolate and/or the desolvatesthereof, and especially the crystalline form S2 can be characterised,alternatively or additionally, by Powder X-Ray Diffraction, morepreferably by the Powder X-Ray Diffraction pattern comprising one ormore of the Powder X-ray peaks given below, more preferably comprising 4or more of the Powder X-ray peaks given below, even more preferably 6 ormore of the Powder X-ray peaks given below, and especially comprisingall of the of the Powder X-ray peaks given below:

a) Miller °2θ (Co—Kα₁ indizes No. D [Å] radiation) ± 0.1° h k l 1 13.327.7 2 0 0 2 12.89 8.0 1 1 0 4 7.87 13.1 0 1 1 5 7.54 13.6 1 1 1 6 7.3614.0 0 2 0 7 5.01 20.6 5 1 0 9 4.82 21.3 1 3 0 10 4.58 22.5 1 0 2or more preferably

b) Miller °2θ (Cu—Kα₁ indizes No. D [Å] radiation) ± 0.1° k l hl 1 13.327.7 2 0 0 2 12.89 8.0 1 1 0 4 7.87 13.1 0 1 1 5 7.54 13.6 1 1 1 6 7.3614.0 0 2 0 7 5.01 20.6 5 1 0 9 4.82 21.3 3 2 1 10 4.58 22.5 1 0 2

Preferably, the tetrasolvates according to the invention, morepreferably the Dihydrate-diethanolate, the Dihydrate-ethanolate, theDihydrate-monoethanolate, the Diethanolate and/or the desolvatesthereof, and especially the crystalline form S2 can be characterised,alternatively or additionally, by Powder X-Ray Diffraction and morepreferably by the Powder X-Ray Diffraction pattern comprising one ormore of the Powder X-ray peaks given below, more preferably comprising10 or more of the Powder X-ray peaks given below, even more preferably12 or more of the Powder X-ray peaks given below, and especiallycomprising all of the of the Powder X-ray peaks given below:

a) Miller D ± 0.1 °2θ (Co—Kα₁ indizes No. [Å] radiation) ± 0.1° h k l 014.73 6.9 0 1 0 1 13.32 7.7 2 0 0 2 12.89 8.0 1 1 0 3 8.78 11.7 1 0 1 47.87 13.1 0 1 1 5 7.54 13.6 1 1 1 6 7.36 14.0 0 2 0 7 7.10 14.5 1 2 0 85.01 20.6 5 1 0 9 4.82 21.3 1 3 0 10 4.58 22.5 1 0 2 11 4.38 23.6 1 1 212 4.28 24.1 1 3 1 13 3.81 27.1 4 0 2 14 3.69 28.0 4 1 2or more preferably

b) Miller D ± 0.1 °2θ (Co—Kα₁ indizes No. [Å] radiation) ± 0.1° k l h 014.73 6.9 0 1 0 1 13.32 7.7 2 0 0 2 12.89 8.0 1 1 0 3 8.78 11.7 1 0 1 47.87 13.1 0 1 1 5 7.54 13.6 1 1 1 6 7.36 14.0 0 2 0 7 7.10 14.5 1 2 0 85.01 20.6 5 1 0 9 4.82 21.3 3 2 1 10 4.58 22.5 1 0 2 11 4.38 23.6 1 1 212 4.28 24.1 1 3 1 13 3.81 27.1 6 2 0 14 3.69 28.0 0 4 0

The Powder X-ray diffractogram of crystalline form S2 is shown in FIG.17

The PXRD pattern can be successfully indexed with the followingorthorhombic unit cell (space group P2₁2₁2₁):

a=9.3 Å, b=26.6 Å, c=14.7 Å (±0.1 Å), V˜3600 (±10) Å³

The Powder X-Ray Diffraction and more preferably the Powder X-RayDiffraction pattern is preferably performed or determined as describedherein and especially performed or determined by standard techniques asdescribed in the European Pharmacopeia 6^(th) Edition chapter 2.9.33,and is even more preferably obtained with the parameters Cu—Kα₁radiation and/or λ=1.5406 Å, preferably on a Stoe StadiP 611 KLdiffractometer.

Preferably, the tetrasolvates according to the invention, morepreferably the Dihydrate-diethanolate, the Dihydrate-ethanolate, theDihydrate-monoethanolate, the Diethanolate and/or the desolvatesthereof, and especially the crystalline form S2 can be characterised,alternatively or additionally, by Single Crystal X-Ray Structure Data,for example Single Crystal X-Ray Structure Data obtained on adiffractometer preferably equipped with a graphite monochromator and CCDDetector, preferably using Mo K_(α) radiation, preferably at atemperature of 298 K±5 K, and even more preferably on a XCaliburdiffractometer from Oxford Diffraction equipped with graphitemonochromator and CCD Detector using Mo K_(α) radiation at about 298 K.

According to the Single Crystal X-Ray Structure Data obtained, thetetrasolvates according to the invention, more preferably theDihydrate-diethanolate, the Dihydrate-ethanolate, the Diethanolateand/or the desolvates thereof, and especially the crystalline form S2,crystallise in the orthorhombic space group P 2₁2₁ 2₁ with the latticeparameters a=9.3 Å, b=26.3 Å, c=13.7 Å (±0.1 Å) and the unit cell volumeis preferably is 3351 (±10) Å³

From the single crystal structure it is obvious that form S2 representsa tetrasolvate according to the invention and more specifically a mixedethanol-water solvate and even more specifically aDihydrate-monoethanolate.

The Single Crystal X-Ray Structure is depicted in FIG. 32.

Preferably, the tetrasolvates according to the invention, morepreferably the Dihydrate-diethanolate, the Dihydrate-ethanolate, theDihydrate-monoethanolate, the Diethanolate and/or the desolvatesthereof, and especially the crystalline form S2 can be characterised,alternatively or additionally, by the infrared-spectroscopy datacomprising one or more of the band positions (±2 cm⁻¹) given below, morepreferably comprising 3 or more of the band positions (±2 cm⁻¹) givenbelow, even more preferably comprising 6 or more of the band positions(±2 cm⁻¹) given below, and especially comprising all the band positions(±2 cm⁻¹) given below, preferably together with the relative intensitiesgiven in brackets:

3306 cm⁻¹ (s), 2968 cm⁻¹ (m), 1668 cm⁻¹ (s), 1546 cm⁻¹ (s), 1395 cm⁻¹(m), 1223 cm⁻¹ (w), 1049 cm⁻¹ (w), 705 cm⁻¹ (w).

More preferably, the tetrasolvates according to the invention, morepreferably the Dihydrate-diethanolate, the Dihydrate-ethanolate, theDihydrate-monoethanolate, the Diethanolate and/or the desolvatesthereof, and especially the crystalline form S2 can be characterised,alternatively or additionally, by the infrared-spectroscopy datacomprising one or more of the band positions (±2 cm⁻¹) given below, morepreferably comprising 6 or more of the band positions (±2 cm⁻¹) givenbelow, even more preferably comprising 9 or more of the band positions(±2 cm⁻¹) given below, and especially comprising all the band positions(±2 cm⁻¹) given below, preferably together with the relative intensitiesgiven in brackets:

3306 cm⁻¹ (s), 2968 cm⁻¹ (m), 2872 cm⁻¹ (m), 1668 cm⁻¹ (s), 1546 cm⁻¹(s), 1452 cm⁻¹ (w), 1395 cm⁻¹ (m), 1223 cm⁻¹ (w), 1086 cm⁻¹ (w), 1049cm⁻¹ (w), 746 cm⁻¹ (w), 705 cm⁻¹ (w).

The relative intensities given in brackets are preferably defined asfollows: *“s”=strong (transmittance preferably ≦50%), “m”=medium(preferably 50%<transmittance≦70%), “w”=weak (transmittance preferably>70%)

The IR or FT-IR spectrum is preferably obtained using a KBr pellet assample preparation technique.

The IR-spectroscopy data is preferably obtained by FT-IR-spectroscopy,The IR-spectroscopy data or FT-IR-spectroscopy data is preferablyobtained by standard techniques as described in the EuropeanPharmacopeia 6^(th) Edition chapter 2.02.24. For the measurement of theFT-IR-spectra, preferably a Bruker Vector 22 spectrometer is used. FT-IRspectra are preferably base-line corrected, preferably using Bruker OPUSsoftware.

The FT-IR spectra of the tetrasolvates according to the invention andespecially the crystalline form S2 is given in FIG. 18.

Preferably, the tetrasolvates according to the invention and, morepreferably the Dihydrate-diethanolate, the Dihydrate-ethanolate, theDihydrate-monoethanolate, the Diethanolate and/or the desolvatesthereof, especially the crystalline form S2 can be characterised,alternatively or additionally, by the Raman-spectroscopy data comprisingone or more of the band positions (±2 cm⁻¹) given below, more preferablycomprising 5 or more of the band positions (±2 cm⁻¹) given below, evenmore preferably comprising 8 or more of the band positions (±2 cm⁻¹)given below, and especially comprising all the band positions (±2 cm⁻¹)given below, preferably together with the relative intensities given inbrackets:

3068 cm⁻¹ (w), 2934 cm⁻¹ (s), 1668 cm⁻¹ (w), 1606 cm⁻¹ (w), 1449 cm⁻¹(w), 1337 cm⁻¹ (w), 1204 cm⁻¹ (w), 1120 cm⁻¹ (w), 1004 cm⁻¹ (m), 904cm⁻¹ (w), 825 cm⁻¹ (w), 624 cm⁻¹ (w), 521 cm⁻¹ (w).

More preferably, the tetrasolvates according to the invention, morepreferably the Dihydrate-diethanolate, the Dihydrate-ethanolate, theDihydrate-monoethanolate, the Diethanolate and/or the desolvatesthereof, and especially the crystalline form S2 can be characterised,alternatively or additionally, by the Raman-spectroscopy data comprisingone or more of the and positions (±2 cm⁻¹) given below, more preferablycomprising 9 or more of the band positions (±2 cm⁻¹) given below, evenmore preferably comprising 12 or more of the band positions (±2 cm⁻¹)given below, and especially comprising all the band positions (±2 cm⁻¹)given below, preferably together with the relative intensities given inbrackets:

3068 cm⁻¹ (w), 2934 cm⁻¹ (s), 1668 cm⁻¹ (w), 1606 cm⁻¹ (w), 1586 cm⁻¹(w), 1449 cm⁻¹ (w), 1337 cm⁻¹ (w), 1204 cm⁻¹ (w), 1120 cm⁻¹ (w), 1033cm⁻¹ (w), 1004 cm⁻¹ (m), 904 cm⁻¹ (w), 825 cm⁻¹ (w), 624 cm⁻¹ (w), 521cm⁻¹ (w).

The relative intensities given in brackets are preferably defined asfollows: “s”=strong (relative Raman intensity preferably ≧0.04),“m”=medium (preferably 0.04>relative Raman intensity≧0.02), “w”=weak(relative Raman intensity preferably <0.02)

The Raman or FT-Raman spectrum is preferably obtained usingAluminium-cups as sample holders for the respective solid material.

The Raman-spectroscopy data is preferably obtained byFT-Raman-spectroscopy, The Raman-spectroscopy data orFT-Raman-spectroscopy data is preferably obtained by standard techniquesas described in the European Pharmacopeia 6^(th) Edition chapter2.02.48. For the measurement of the FT-Raman-spectra, preferably aBruker RFS 100 spectrometer is used. FT-Raman spectra are preferablybase-line corrected, preferably using Bruker OPUS software.

The FT-Raman spectra of the tetrahydrates according to the invention,more preferably the Dihydrate-diethanolate, the Dihydrate-ethanolate,the Dihydrate-monoethanolate, the Diethanolate and/or the desolvatesthereof, and especially the crystalline form S2 is given in FIG. 19.

Preferably, the tetrasolvates according to the invention, morepreferably the Dihydrate-diethanolate, the Dihydrate-ethanolate, theDihydrate-monoethanolate, the Diethanolate and/or the desolvatesthereof, and especially the crystalline form S2 can be characterised,alternatively or additionally, by dynamic vapour experiments using watervapour and/or methanol vapour. The results can be obtained by standardtechniques as described in Rolf Hilfiker, ‘Polymorphism in thePharmaceutical Industry’, Wiley-VCH. Weinheim 2006 (Chapter 9: WaterVapour Sorption, and references therein).

The Water Vapour Sorption behaviour of the tetrasolvates according tothe invention, more preferably the Dihydrate-diethanolate, theDihydrate-ethanolate, the Dihydrate-monoethanolate, the Diethanolateand/or the desolvates thereof, and especially the crystalline form S2shows a mass loss of approx. 6.5 wt % in the first desorption cycle(which is lower than the observed Ethanol mass gain in the EthanolVapour Sorption experiment). Upon water vapour adsorption, an assemblyof water molecules in the lattice is observed, with a maximum weightgain of approx. 6.4 wt % at elevated rh. In the second desorption cyclea total mass loss of approx. 9.2 wt % is observed. For a DihydrateDi-Ethanolate of the compound of formula I, the calculated Ethanolcontent equals 12.5 wt %. Form S2 can be shown to be thethermodynamically stable form in an atmosphere of 100% Ethanol vapour.The Water Vapor Sorption isotherm (25° C.) of crystalline form S2 (SMSDVS Intrinsic) is given in FIG. 20. The Ethanol Vapour Sorption Isotherm(25° C.) of a hydrate form to form S2 (SMS DVS Advantage) is given inFIG. 21.

Thus, crystalline form S2 is a crystalline Ethanol solvate form or amixed water/ethanol solvate form, preferably selected from theDihydrate-ethanolate, the Dihydrate-monoethanolate, the Diethanolateand/or the desolvates thereof, which can be obtained e.g. via EthanolVapour Sorption, preferably via Ethanol Vapour Sorption starting with ahydrate structure, such as the hydrates according to the invention andespecially the tetrahydrate according to the invention, i.e. crystallineform S3. From the Ethanol Vapour Sorption curve as shown in FIG. 21 andas discussed above, it can be seen that at elevated Ethanol partialpressure, approx. 17 wt % Ethanol are taken up by the sample.

As can be seen from the data given and discussed herein, the solvatesand especially the tetrasolvates of the compound of formula I form aclass of novel crystalline forms (further also to be namedpseudopolymorphic forms or abbreviated PP) based on the same structuraltype, having highly similar physical properties and being easilyconvertible, preferably with potentially all transition forms beingderivable and especially all transition forms between thepseudopolymorphic forms described herein being potentially derivable.

The similarity of the structural type is additionally shown by asuperimposed plot of PXRD patterns of the three selected pseudopolymophsS1, S2 and S3 given in FIG. 22. It can be seen that all three selectedpseudopolymorphs exhibit very similar PXRD patterns, and, moreover, leadto basically same unit cells, as a replacement of water by Methanol orEthanol only leads to a slight expansion of the unit cells and thus to aslight increase in unit cell volume. As expected from the molar volumesof the solvents, this is more pronounced for the Ethanol solvate thanfor the Methanol solvate.

In the presence of alcohols, preferably Methanol and/or Ethanol, and/orwater being present in different concentrations or partial pressuresinterconversion within the pseudopolymorphic class, comprising thesolvates and especially the tetrasolvates according the invention,occurs easily. As alcohols, preferably Methanol and/or Ethanol, areuseful solvents in the manufacturing process, usage of thepseudopolymorphs is preferably beneficial to obtain the compound offormula I in a crystalline solid-state modification exhibiting anadvantageously high solubility combined with good crystallinity.

The solvates and especially the tetrasolvates within thepseudopolymorphic class or system are crystalline and preferably exhibitadvantageous solid-state stability without loss of the Cilengitide hoststructure, in comparison to the previously described amorphous solidmaterial. Said class of pseudopolymorphic forms described herein exhibita surprisingly high solubility, especially in aqueous media, which makesthem especially useful for preparation of liquid formulations.Additionally, said class of polymorphic forms show a advantageouslyreduced hygroscopicity in comparison to the previously known amorphousmaterial.

Solubility of tetrahydrate Form S3 in different solvents:

Solvent Solubility H₂O 21.6 mg/ml physiological NaCl solution 21.1 mg/mlbuffer pH 7.4 24.4 mg/ml H₂O/MeOH (1:1) 12.8 mg/ml H₂O/EtOH (1:1) 13.0mg/ml H₂O/iPrOH (1:1) 22.9 mg/ml H₂O/Acetone (1:1) 22.7 mg/mlH₂O/Acetonitrile (1:1) 24.3 mg/ml

The combination of reduced hygroscopicity, good solubility and goodcrystallinity leads to superior properties compared to the amorphousphase. In comparison, the purification, the handling and the processingof the amorphous material is very difficult, due to, e.g. the very highhygroscopicity and the low stability of the amorphous solid material.

Further, the pseudopolymorphic forms and/or the anhydrates or ansolvatesaccording the invention show improved physical and/or chemical stabilitycompared to the amorphous phase, preferably leading to a reducedformation of degradation products during storage, for example byhydrolysis. This improved hydrolytic stability of the solid materialaccording to the invention and especially of the crystalline formsaccording to the invention is believed to be caused by the reduction oftrace amounts of ionic impurities that are normally present in theamorphous material of prior art.

As a result, all those factors discussed herein are believed to accountfor the advantageously improved solid state stability of the solidmaterial according to the invention, the crystalline forms according tothe invention and especially of the solvates and/or anhydrates oransolvates according to the invention.

Additionally, all those factors discussed herein are believed to accountfor the advantageously improved stability of the medicaments accordingto the invention that contain the solid material according to theinvention, preferably the crystalline forms according to the inventionand especially the solvates and/or anhydrates or ansolvates according tothe invention, leading e.g. to a longer shelf life due to higher thermaland/or storage stability.

A preferred subject of the invention is a solid material as describedabove and/or below for the treatment of disorders.

Disorders in this regard are preferably selected from group consistingof cancerous disorders, angiogenesis or angiogenic disorders, autoimmunedisorders, inflammatory disorders and ocular disorders, and morepreferably from the group consisting of brain cancer, lung cancer, headand neck cancer, breast cancer and prostate cancer, and metastasesthereof, arthritis, rheumatoid arthritis, psoriasis, retinopathy,diabetic retinopathy, atherosclerosis, macular degeneration and agerelated macular degeneration.

Especially preferred is a solid material as described above and/or belowfor the treatment of disorders, selected from cancerous disorders.

Especially preferred is a solid material as described above and/or belowfor the treatment of cancerous disorders, wherein the cancerousdisorders are selected from the group consisting of brain cancer, lungcancer, head and neck cancer, breast cancer and prostate cancer, andmetastases thereof.

A preferred subject of the instant invention is a method of treatingcancerous disorders in a patient, comprising administering to saidpatient a solid material as described above and/or below.

Especially preferred is a method as described above, wherein thecancerous disorders are selected from one or more of the groups ofdisorders described above.

A preferred subject of the instant invention is the use of a solidmaterial according to the invention for the manufacture of a medicamentfor the treatment of disorders. Preferably, the disorders are selectedfrom one or more of the groups of disorders described above.

Thus, a preferred subject of the instant invention is the use of a solidmaterial essentially consisting of or consisting of one or morecrystalline forms according to the invention, for the manufacture of amedicament for the treatment of disorders, preferably disorders asdescribed herein.

An even more preferred subject of the instant invention is the use of asolid material essentially consisting or consisting of one or morecrystalline forms, selected from the group consisting of crystallineform A1, crystalline form S1, crystalline form S2 and crystalline formS3, and mixtures thereof, for the manufacture of a medicament for thetreatment of disorders, preferably disorders as described herein.

Especially preferred subject of the instant invention is the use of asolid material especially consisting or consisting of crystalline formA1 or crystalline form S3, or mixtures thereof, for the manufacture of amedicament for the treatment of disorders, preferably disorders asdescribed herein.

Surprisingly, the solid material according to the invention andespecially the one or more crystalline forms according to the inventioncan be prepared by contacting the compound according to formula I with asolvent or solvent mixture, preferably a polar and/or protic solvent orsolvent mixture.

Thus, a preferred subject of the instant invention is a process for thepreparation or manufacture of the solid material according to theinvention and especially for the preparation or manufacture of one ormore of the crystalline forms according to the invention, comprisingcontacting a compound according to formula I with a solvent or solventmixture, preferably a polar and/or protic solvent or solvent mixture,and isolating the solid material according to the invention obtained bysaid contacting from said solvent or solvent mixture.

Said isolation from said solvent or solvent is preferably achieved by

-   i) crystallisation and/or precipitation of the solid material    according to the invention from said solvent or solvent mixture,    and/or-   ii) separating the solid material according to the invention from    said solvent, preferably by physical means, such as filtration or    centrifugation, or alternatively by sedimentation and/or decanting.

However, a plurality of separation techniques for achieving asolid/fluid separation are known in the art. Preferably, either one ofthem can be successfully applied for said separation.

Preferably, the solid material according to the invention and especiallythe one or more crystalline forms according to the invention can beprepared starting with a solid material of the compound according toformula I that is essentially free or preferably free of one or more ofthe crystalline forms according to the invention, and then by contactingit with a solvent or solvent mixture, preferably a polar and/or proticsolvent or solvent mixture.

Alternatively preferably, the solid material according to the inventionand especially the one or more crystalline forms according to theinvention can be prepared starting with a solution of the compoundaccording to formula I that is essentially free or preferably free ofone or more of the crystalline forms according to the invention, andthen by contacting it with a solvent or solvent mixture, preferably apolar and/or protic solvent or solvent mixture, or transferring saidsolution of the compound according to formula I that is essentially freeor preferably free of one or more of the crystalline forms according tothe invention into said solvent or solvent mixture, preferably saidpolar and/or protic solvent or solvent mixture.

Generally, to obtain the solid form according to the invention and/orone or more of the crystalline forms according to the invention, thecontacting with said solvent or solvent mixture, preferably said polarand/or protic solvent or solvent mixture or the contact with saidsolvent or solvent mixture, preferably said polar and/or protic solventor solvent mixture is followed by an isolating step, wherein the solidmaterial according to the invention and/or one or more of thecrystalline forms according to the invention can be obtained in a solidstate.

Contacting or contact in this regard preferably means contacting in thebroadest sense, such as “being in the presence of”. Accordingly,examples of contacting or contact with said solvent or solvent mixtureinclude, but are not limited to, dissolving or partly dissolving in saidsolvent or solvent mixture, suspending in said solvent or solventmixture, stirring in the presence of said solvent or solvent mixture,triturating with or in the presence of said solvent or solvent mixture,allowing to stand in the presence of said solvent or solvent mixture,heating in the presence of said solvent or solvent mixture, cooling inthe presence of said solvent or solvent mixture, crystallising orre-crystallising from said solvent or solvent mixture and/orprecipitating from said solvent or solvent mixture.

Preferred ways of contacting or contact in this regard are preferablyselected from a group consisting of: dissolving or partly dissolving insaid solvent or solvent mixture, stirring in the presence of saidsolvent or solvent mixture, triturating with or in the presence of saidsolvent or solvent mixture, heating or cooling, preferably heating inthe presence of said solvent or solvent mixture, crystallising orre-crystallising from said solvent or solvent mixture and/orprecipitating from said solvent or solvent mixture.

An especially preferred way of contacting in this regard comprisesdissolving, essentially dissolving or suspending the starting materialof the compound of formula I and/or salts thereof in a (first) polarand/or protic solvent or solvent mixture, preferably followed byre-crystallising, crystallising and/or precipitating of the productformed from said solventor solvent mixture, which is preferably a solidmaterial according to the invention. Preferably, re-crystallisation,crystallisation and/or precipitation of the product formed is induced orfacilitated by cooling and/or the addition of further (or second)solvent or solvent mixture, preferably a further solvent or solventmixture having a different polarity and more preferably having a lowerpolarity than the (first) solvent or solvent mixture in which thecontacting was started. Another especially preferred way of contactingin this regard comprises the formation of a slurry of the startingmaterial of the compound of formula I as described above and/or belowand a polar and/or protic solvent or solvent mixture, and stirringand/or agitating said slurry, preferably for a reaction time asdescribed herein and a reaction temperature or processed temperature asdescribed herein. This is preferably also referred to as “slurryconversion”

Suitable solvents and solvent mixtures for use in the methods and/orprocesses according to the invention are known in the art. Preferredsolvents and solvent mixtures are preferably selected from the groupconsisting of organic solvents, water, saline, buffer solutions, andmixtures thereof. The terms “polar and/or protic solvent or solventmixture” are known and clear to the ones skilled in the art.

Examples polar and/or protic solvents include, but are not limited to,water, saline or physiological NaCl solution, phosphate buffer solution,lower alcohols, such as monools, diols or triols having 1 to 6 carbonatoms, lower ketones, such as acetone or methyl ethly ketone,acetonitrile, propionitrile, DMF, DMSO, and the like. Preferred polarand/or protic solvents are selected from the group consisting of water,saline, methanol, ethanol, propanol, isopropanol, acetone, acetonitrile,propionitrile, DMF and DMSO.

Examples of polar and/or protic solvent mixtures include, but are notlimited to, mixtures of the above given polar and/or protic solvents,more preferably mixtures of water with one or more of the above givenpolar and/or protic solvents other than water, mixtures of saline orphysiological NaCl solution or phosphate buffer solution with one ormore of the above given polar and/or protic solvents.

Preferred polar and/or protic solvent mixtures are selected from thegroup consisting of mixtures of water with methanol, ethanol and/orisopropanol, mixtures of methanol, ethanol and/or isopropanol, mixturesof acetone with water and/or acetonitrile, mixtures of methanol withacetone, acetonitrile and/or water, and mixtures of ethanol withacetone, acetonitrile, and preferably also selected from the above givenmixtures, wherein the water is substituted for saline, physiologicalNaCl solution, or phosphate buffer solution. Preferred within saidmixtures are mixtures comprising all preferably essentially consistingof 2, 3 or 4 of the given solvents. Especially preferred within saidmixtures are mixtures that comprise at least 5% and especially at least10% of each of the solvents contained in the mixture.

Examples of preferred solvents and/or solvent mixture in this regard areselected from the group consisting of water, methanol, ethanol,isopropanol, and mixtures thereof, more preferably selected from thegroup consisting of water, methanol, ethanol, and mixtures thereof.

In said method of manufacture of a solid material according to theinvention, the starting material of compound of formula I is preferablyselected from the group consisting of

a) amorphous or essentially amorphous material of the compound offormula I,b) an acid-addition or a base-addition salt of the compound of formulaI,c) an amorphous or essentially amorphous solid material of anacid-addition or a base-addition salt of the compound of formula I, andb) a solution of crude compound of formula I and/or an acid-addition ora base-addition salt thereof, preferably as obtained from the synthesisof said compound and/or salt thereof,and mixtures thereof.

Additionally, it was surprisingly found that one first crystalline formaccording to the invention can be transformed into one or more othercrystalline forms according to the invention, preferably reversibly.Furthermore, it was found that one first mixture of one or morecrystalline forms according to the invention can be either transformedinto a second mixture of crystalline forms according to the inventionbeing different from said first mixture, or into a pure or essentiallypure singer crystalline form according to the invention.

Accordingly, the invention also provides a process for transforming onefirst solid material according to the invention, comprising one or morefirst crystalline forms, into a second solid material according to theinvention, comprising one or more second crystalline forms. This methodcan be preferably done in the same way and preferably using the samesolvent and/or solvent mixtures as the method of manufacture describedabove and/or below, but is using a (first) solid material according tothe invention as the starting material of the method.

Thus, a preferred subject of the instant invention is a process for themanufacture or the transformation, preferably manufacture, of a solidmaterial according to the invention, comprising

a) contacting cyclo-(Arg-Gly-Asp-DPhe-NMeVal) and/or an acid-addition ora base-addition salt thereof with a solvent or solvent mixture,preferably a polar and/or protic solvent or solvent mixture,b) precipitating and/or crystallising the internal salt ofcyclo-(Arg-Gly-Asp-DPhe-NMeVal) from a polar and/or protic solvent orsolvent mixture, andc) optionally isolating a solid material according the invention.

In said process for the transformation, the starting material employedin step a) is preferably a (first) solid form according to theinvention, containing cyclo-(Arg-Gly-Asp-DPhe-NMeVal) as the inner salt,and the solid material according to the invention obtained under step b)and optionally isolated according to step c) is a (second) differentsolid material according to the invention. Preferably, the differencebetween the first solid material according to the invention and thesecond different solid material according to the invention is the amountof crystalline forms contained in said second solid form, the selectionof the crystalline forms contained in said solid form or the ratio ofthe crystalline forms contained in said solid form.

In said process for the manufacture, the starting material employed instep a) is preferably selected from

-   i) a solid form of the compound of formula I different from the    solid form according to the invention,-   ii) a solution of cyclo-(Arg-Gly-Asp-DPhe-NMeVal) and/or an    acid-addition or a base-addition salt thereof, wherein the solution    is preferably either a crude solution or obtained, more preferably    directly obtained, from the synthesis of the    cyclo-(Arg-Gly-Asp-DPhe-NMeVal), and/or-   iii) obtained from dissolving a solid form of the compound of    formula I different from the solid form according to the invention.

Thus, a preferred subject of the instant invention is a process for themanufacture of a solid material according to the invention, comprising

a) contacting an acid-addition or a base-addition salt ofcyclo-(Arg-Gly-Asp-DPhe-NMeVal) with a polar and/or protic solvent orsolvent mixture,b) precipitating and/or crystallising the internal salt ofcyclo-(Arg-Gly-Asp-DPhe-NMeVal) from a polar and/or protic solvent orsolvent mixture, andc) optionally isolating a solid material according the invention.

In said process for the manufacture and/or the transformation, step a),b) and/or c) is preferably performed at a pH value in the range of 5.5to 8, more preferably at a pH value in the range of 6 to 7.5, morepreferably at a pH value in the range of 6.5 to 7.2 and especially at apH value in the range of 6.7 to 6.9, for example at a pH value of about6.8. More preferably, two or more of the steps selected from a), b) andc) are performed at the pH values given above, and especially all thesteps a), b) and c) are performed at the pH values given above.Performing one or more of the steps selected from a), b) and c) at thepH values given above is advantageous to convert an acid-addition or abase-addition salt of cyclo-(Arg-Gly-Asp-DPhe-NMeVal) into the innersalt of cyclo-(Arg-Gly-Asp-DPhe-NMeVal), or to maintain or stabilize theinner salt of cyclo-(Arg-Gly-Asp-DPhe-NMeVal) within said process.

In said process for the manufacture and/or the transformation, step a),b) and/or c) is preferably performed under about isoelectric conditions.More preferably, two or more of the steps selected from a), b) and c)are performed under about isoelectric conditions, and especially all thesteps a), b) and c) are performed under about isoelectric conditions.Performing one or more of the steps selected from a), b) and c) underabout isoelectric conditions is also advantageous to convert anacid-addition or a base-addition salt of cyclo-(Arg-Gly-Asp-DPhe-NMeVal)into the inner salt of cyclo-(Arg-Gly-Asp-DPhe-NMeVal), or to maintainor stabilize the inner salt of cyclo-(Arg-Gly-Asp-DPhe-NMeVal) withinsaid process.

In said process for the manufacture and/or the transformation, step a),b) and/or c) is preferably performed at a temperature in the rangebetween −20° C. and +200° C., more preferably in the range between −5°C. and +150° C., even more preferably in the range between +5° C. and+110° C. and especially in the range between +10° C. and +100° C., forexample at about room temperature (about 25° C.), at about 50° C. or atabout 75° C. or at about 100° C.

Generally, higher temperatures tend to accelerate the processes for themanufacture and/or the processes for the transformation as describedherein.

Generally, temperatures at the higher end of the given temperatureranges tend to promote the formation the anhydrates or ansolvatesaccording to the invention.

Generally, temperatures at the lower end of the given temperature rangestend to promote the formation of the solvates according to theinvention.

In the processes for the manufacture of the solid materials according tothe invention and/or in the processes for the conversion ortransformation of the solid materials according to the invention and/orto crystallise form according to the invention, the processing time or“reaction time”, i.e. the time during which the contacting, theprecipitation, the crystallization and/or the isolation preferably takesplace is generally between five minutes to four weeks. Said processingtime is preferably not a very crucial factor for the processes accordingto the invention since during the above given times, very little or nodecomposition of the compound according to formula I takes place,especially within the preferred process parameters or process conditionsdescribed herein. Additionally, the product of the process, i.e. thesolid material according to the invention, is generally stable under theconditions it is formed.

Accordingly, processing times preferably are the range of 10 minutes tothree weeks, more preferably 15 minutes to one week, more preferably 30minutes to 72 hours and especially one hour to 48 hours.

Processing times for the formation or conversion, preferably formation,of the anhydrates or ansolvates according to the invention, andespecially for the formation of the crystalline form A1 are preferablyin the range of one hour to three weeks, more preferably in the range ofone hour to two weeks and especially in the range of one hour to 72hours.

Processing times for the formation or conversion, preferably formation,of the solvates according to the invention, more preferably thetetrasolvates according to the invention, even more preferably the oneor more crystalline forms S1, S2 and/or S3 and especially for theformation of the crystalline form S1 are preferably in the range of fiveminutes to three weeks, more preferably in the range of five minutes toone week, even more preferably in the range of five minutes to 48 hoursand especially in the range of 10 minutes to 24 hours.

Generally, lower temperatures during said processes lead to longerprocessing times, as it is known in the art.

Generally, water, methanol and/or ethanol, and mixtures thereof arepreferred polar and/or protic solvents or solvent mixtures for use instep a), b) and/or c) and especially for use in step a), b) and c).

In said process for the manufacture and/or the transformation, thesolvent of step a), b) and/or c), preferably a), b) and c), essentiallyconsists of water, methanol or ethanol.

Preferably, the same or essentially the same solvent or solvent mixture,preferably a polar and/or protic solvent or solvent mixture is used inprocess steps a), b) and c).

Generally, the use of solvent or solvent mixtures in step a), b) and/orc) that contain at least 5% by weight, more preferably at least 10% byweight and especially at least 20% by weight of one or more alcohols,preferably selected from methanol, ethanol and isopropanol, morepreferably selected from methanol and ethanol, promote the formation ofthe solvates according to the invention.

More specifically, the use of solvent mixtures in step a), b) and/or c)that comprise

i) 5 to 90% by weight of at least one alcohol, selected from the groupconsisting of methanol and ethanol, andii) 10 to 95% by weight of water,preferably promote the formation of the solvates according to theinvention.

Even more specifically, the use of solvent mixtures in step a), b)and/or c) that comprise

i) 5 to 50% by weight and especially 10 to 60% by weight of at least onealcohol, preferably selected from the group consisting of methanol andethanol, andii) 50 to 95% by weight and especially 40 to 90% by weight of water,preferably promote the formation of the solvates according to theinvention.

Thus, preferred is a process as described above and/or below for themanufacture of a solid material according to the invention, preferablysolvates according to the invention, and especially of one or moretetrasovates according to the invention, wherein the solvent or solventmixture of step a), b) and/or c) comprises

i) 5 to 90% by weight, preferably 5 to 50% by weight, of at least onealcohol, selected from the group consisting of methanol and ethanol, andii) 10 to 95% by, weight preferably 50 to 95% by weight, of water.

Thus, preferred is a process as described above and/or below for themanufacture of a solid material according to the invention, preferablyanhydrates or ansolvates according to the invention, and especially ofcrystalline form A1, wherein solvent of step a), b) and/or c)essentially consists of water, methanol and ethanol and more preferablyessentially consists of water.

Thus, preferred is a process as described above and/or below for themanufacture of a solid material according to the invention, preferablyanhydrates or ansolvates according to the invention, and especially ofcrystalline form A1, wherein steps a), b) and/or c) are performed at atemperature above +40° C., more preferably at a temperature of +50° orhigher and especially at a temperature of +60° or higher.

Within the process parameters that are preferred for the formation ofsolvates and especially tetrasolvates according to the invention, analcohol content at the lower end of the given ranges and/or a watercontent at the higher end of the given ranges promote the formation ofthe hydrates according to the invention. Alternatively, an alcoholcontent at the higher end of the given ranges and/or a water content atthe lower end of the given ranges promote the formation of alcoholsolvates.

Especially preferred solvates in this regard are the tetrasolvates,preferably selected from the tetrahydrate, the methanol solvates and theethanol solvates, and mixed forms thereof, even more preferably selectedfrom the tetrahydrate, the methanol solvate S1 and the ethanol solvateS2, and especially the tetrahydrate S3.

Thus, one preferred process for the manufacture of a solid materialaccording to the invention comprises or preferably essentially consistsof

-   i) crystallising or re-crystallising an amorphous material or an    essentially amorphous material of the compound of formula I from a    solvent or solvent mixture, preferably a polar and/or protic solvent    or solvent mixture, preferably a solvent or solvent mixture,    preferably a polar and/or protic solvent or solvent mixture as    described herein, and optionally-   ii) isolating the thus obtained solid material according to the    invention from said solvent or solvent mixture by a solid/fluid    separation technique, preferably a solid/fluid separation technique    as described herein and especially by filtration.

Thus, one preferred process for the transformation of a first solidmaterial according to the invention into a second solid materialaccording to the invention comprises or preferably essentially consistsof

-   a) precipitating, crystallising or re-crystallising a first solid    material according to the invention from a solvent or solvent    mixture, preferably a polar and/or protic solvent or solvent    mixture, preferably a solvent or solvent mixture, preferably a polar    and/or protic solvent or solvent mixture as described herein, and    optionally-   b) isolating the thus obtained second solid material according to    the invention from said solvent or solvent mixture by a solid/fluid    separation technique, preferably a solid/fluid separation technique    as described herein and especially by filtration.

In the synthesis of the compound cyclo-(Arg-Gly-Asp-DPhe-NMe-Val), thefinal product or crude product of said synthesis is in many cases anacid-addition or a base-addition salt of the compoundcyclo-(Arg-Gly-Asp-DPhe-NMe-Val), preferably an acid-addition salt ofthe compound cyclo-(Arg-Gly-Asp-DPhe-NMe-Val), e.g. the hydrochloridesalt of cyclo-(Arg-Gly-Asp-DPhe-NMe-Val)(=cyclo-(Arg-Gly-Asp-DPhe-NMe-Val) x HCl), the trifluoroacetic acid saltof cyclo-(Arg-Gly-Asp-DPhe-NMe-Val)(=cyclo-(Arg-Gly-Asp-DPhe-NMe-Val)×TFA), the sulphate salt ofcyclo-(Arg-Gly-Asp-DPhe-NMe-Val) (=cyclo-(Arg-Gly-Asp-DPhe-NMe-Val)×SO₄or, more specifically cyclo-(Arg-Gly-Asp-DPhe-NMe-Val)×0.5 SO₄), ormixtures thereof.

Thus, preferred examples of processes for the manufacture of the solidmaterial according to the invention start from said crude product in theform of acid-addition or a base-addition salts, preferably acid-additionsalts.

Thus, a preferred subject of the instant invention is a process for themanufacture of a solid material according to the invention, comprising:

-   a) contacting an acid-addition or a base-addition salt, preferably    an acid-addition salt, of the compound    cyclo-(Arg-Gly-Asp-DPhe-NMe-Val) with a polar and/or protic solvent    or solid mixture, preferably as defined herein, preferably by    dissolving and/or suspending said salt in said solvent,-   b) converting said salt into the free base or preferably the    internal salt of the compound cyclo-(Arg-Gly-Asp-DPhe-NMe-Val),    preferably by adjusting the pH value, and-   c) crystallising and/or precipitating, and optionally isolating, the    thus obtained solid material according to the invention from said    solvent or solvent mixture.

Thus, a more preferred subject of the instant invention is a process forthe manufacture of a solid material according to the invention,comprising:

-   a) contacting an acid-addition or a base-addition salt, preferably    an acid-addition salt, of the compound    cyclo-(Arg-Gly-Asp-DPhe-NMe-Val) with a solvent or solvent mixture,    preferably a polar and/or protic solvent or solvent mixture,    essentially consisting of or consisting of water, preferably by    dissolving and/or suspending said salt in said solvent,-   b) converting said salt into the free base or preferably the    internal salt of the compound cyclo-(Arg-Gly-Asp-DPhe-NMe-Val),    preferably by adjusting the pH value, and-   c) preferably crystallising and/or precipitating, and optionally    isolating, the thus obtained solid material according to the    invention from said solvent or solvent mixture.

This process is advantageous for the manufacture of solid materialsaccording to the invention that essentially consist of or preferablyconsist of the anhydrates or ansolvates according to the invention andespecially essentially consist of or preferably consist of thecrystalline form A1.

Thus, another more preferred subject of the instant invention is aprocess for the manufacture of a solid material according to theinvention, comprising:

-   a) contacting an acid-addition or a base-addition salt, preferably    an acid-addition salt, of the compound    cyclo-(Arg-Gly-Asp-DPhe-NMe-Val) with a polar and/or protic solvent    or solvent mixture,    -   wherein said solvent or solvent mixture is selected    -   from water and mixtures of 60 to 99.9% per weight water and 0.1        to 40% per weight of at least one alcohol, preferably selected        from methanol and ethanol,    -   and more preferably wherein said solvent or solvent mixture is        water, preferably by dissolving and/or suspending said salt in        said solvent or solvent mixture,-   b) converting said salt into the free base or preferably the    internal salt of the compound cyclo-(Arg-Gly-Asp-DPhe-NMe-Val),    preferably by adjusting the pH value, and-   c) crystallising and/or precipitating the thus obtained solid    material according to the invention, preferably by adding alcohol,    preferably methanol and/or ethanol, to said solvent or solvent    mixture until the weight ratio between water and alcohol in the    resulting solvent mixture is between about 1:1 and about 1:9, and    optionally isolating said solid material from said resulting solvent    mixture.

This process is advantageous for the manufacture of solid materialsaccording to the invention that essentially consist of or preferablyconsist of the solvates according to the invention and especiallyessentially consist of or preferably consist of one or more of thecrystalline forms S1, S2 and S3, preferably includingmixed-water-alcohol solvates of various stoichiometries.

Preferred solvents or solvent mixtures, preferably polar and/or proticsolvents or solid mixtures, pH values to be adjusted as well astemperatures for the above described processes are given and discussedherein.

A preferred example or embodiment of the process steps a), b) and/or c)is comprises the conditioning as described herein. More preferably, thecontacting and/or converting steps can be regarded as conditioning orconditioning steps as described herein.

A preferred form of the process as described above comprises theconditioning or one or more conditioning steps as described herein.

A preferred form of the process as described above essentially consistsof the conditioning or one or more conditioning steps as describedherein.

Preferred parameters for a process for the manufacture of a solidaccording to the invention or a process for the transformationconversion of one or more crystalline forms according to the inventionare presented by the below graphically depicted results of the followingslurry conversion experiments.

The first set of two diagrams given below shows the parameters andresults of competitive slurries in MeOH/water-mixtures at RT (25° C.) asa function of the methanol content in the respective mixture and therespective processing time, i.e. after one day and after three weeks:

Based on additional PXRD investigations it has been shown that theresidues obtained from the competitive slurries represented solvatesincluding water and methanol. Accordingly, the residues have later beendenominated S1 (indicated in the second diagram) instead of S3(indicated in the first diagram).

The second set of two diagrams given below shows the parameters andresults of competitive slurries in EtOH/water-mixtures at RT (25° C.) asa function of the ethanol content in the respective mixture and therespective processing time, i.e. after one day and after three weeks:

Based on additional PXRD investigations it has been shown that theresidues obtained from the competitive slurries represented solvatesincluding water and ethanol. Accordingly, the residues have later beendenominated S2 (indicated in the second diagram) instead of S3(indicated in the first diagram).

Especially preferred processes for the manufacture, processes for thetransformation or conversion and additionally preferred temperatures,solvents, solvent mixtures, reaction times, starting materials and/oradditional process parameters are given in the examples. Thus, theexamples provide sufficient guidance, together with the description ofthe instant invention and/or the claims, to carry out the invention inits full breadth. However, processes and especially process parameterscan be taken out of the examples, as well individually as incombinations of one or more of those processes and/or parameters, andused together with the disclosure in the description and/or claims.

Additionally, higher crystalline solvate forms could be obtained whichcontain up to about seven solvent molecules per molecule of the compoundof formula I in the respective unit cells, and preferably the desolvatesthereof. These higher crystalline solvate forms are preferably referredto as heptasolvates. The unit cell of these heptasolvates preferablycontains about four molecules of the compound of formula I. Preferably,the solvent molecules contained in these heptasolvates are selected fromwater and alcohols and more preferably selected from water, methanol andethanol, and mixtures thereof. Especially preferably, the solventmolecules in said heptasolvates consist essentially of water.

Thus, these higher crystalline solvate forms are preferably referred toas the heptasolvates (according to the invention), more preferably theheptahydrate (according to the invention), and the desolvates thereof,and especially as the crystalline form H1. The heptasolvates accordingto the invention are preferably characterised by a unit cell comprisingof about four molecules of the compound according to formula I and up toabout 7 solvent molecules per molecule of the compound of formula I. Theheptasolvates according to the invention are more preferably representedby a unit cell comprising or preferably essentially consisting of aboutfour molecules of the compound according to formula I and an upper limitof about 7 solvent molecules per molecule of the compound of formula I.Heptasolvates or heptahydrates according to the invention are preferablyalso the desolvates thereof, as long as the original crystal structureof the respective heptasolvate is essentially retained.

The heptasolvates according to the invention, more preferably theheptahydrates according to the invention and the desolvates thereof, andespecially crystalline form H1 is preferably characterised,alternatively or additionally, by a unit cell with the unit cell latticeparameters (ULP) ULP3:

a1=8.1±0.5 Å,

b1=12.9±0.7 Å

and

c1=35.4±1.5 Å,

more preferably by a unit cell with the unit cell lattice parameters(ULP) ULP3:

a1=8.1±0.3 Å,

b1=12.9±0.5 Å

and

c1=35.4±1.0 Å,

and especially by a unit cell with the unit cell lattice parameters(ULP) ULP3:

a1=8.1±0.1 Å,

b1=12.9±0.1 Å

and

c1=35.4±0.1 Å.

In the unit cell with lattice parameters ULP3, the angle α preferably is90°±2°, the angle β preferably is 90°±2° and/or the angle γ preferablyis 90°±2°.

Preferably, the unit cell with lattice parameters ULP3 can becharacterised, alternatively or additionally, preferably additionally,by a content of about 4 molecules of the compound of formula I withinsaid unit cell.

Preferably, the unit cell with lattice parameters ULP3 can becharacterised, alternatively or additionally, preferably additionally,by an upper limit for the content of solvent molecules, preferably watermolecules, of about 7 solvent molecules, preferably water molecules, permolecule of the compound of formula I within said unit cell.

Thus, said unit cell can preferably characterised, alternatively oradditionally, by a total content of about four molecules of the compoundof formula I and a total content or upper limit of 28 solvent molecules,preferably water molecules.

In the unit cell with lattice parameters ULP3, the angle α preferably is90°±0.5°, the angle β preferably is 90°±0.5° and/or the angle γpreferably is 90°±0.5°. In the unit cell with lattice parameters ULP3,the angles α, β and γ more preferably are 90°±0.1°.

The heptasolvates according to the invention, more preferably theheptahydrates according to the invention and the desolvates thereof, andespecially crystalline form H1 can be characterised, alternatively oradditionally, by a melting/decomposition temperature.

The melting/decomposition temperatures and/or thermal behaviors can bepreferably determined by DSC (Differential Scanning Calorimetry) and TGA(ThermoGravimetric Analysis). DSC and/or TGA methods or generallythermoanalysis methods and suitable devices for determining them areknown in the art, for examples from European Pharmacopeia 6^(th) Editionchapter 2.02.34, wherein suitable standard techniques are described.More preferably, for the melting/decomposition temperatures or behaviorsand/or the thermoanalysis in general, a Mettler Toledo DSC 821 and/orMettler Toledo TGA 851 can be used, preferably as described in theEuropean Pharmacopeia 6^(th) Edition chapter 2.02.34.

Preferably, the heptasolvates according to the invention, morepreferably the heptahydrates according to the invention and thedesolvates thereof, and especially crystalline form H1, can becharacterised, alternatively or additionally, by Single Crystal X-RayStructure Data, for example Single Crystal X-Ray Structure Data obtainedon a diffractometer preferably equipped with a graphite monochromatorand CCD Detector, preferably using Mo K_(α) radiation, preferably at atemperature of 302 K±5 K, and even more preferably on a XCaliburdiffractometer from Oxford Diffraction equipped with graphitemonochromator and CCD Detector using Mo K_(α) radiation at about 302 K.

According to the Single Crystal X-Ray Structure Data obtained, theheptasolvates according to the invention, more preferably theheptahydrates according to the invention and the desolvates thereof, andespecially crystalline form H1 crystallises in the orthorhombic spacegroup P 2₁ 2₁ 2₁ with the lattice parameters a=8.1±0.1 Å, b=12.9±0.1 Å,c=35.4±0.1 Å, and the unit cell volume preferably is 3728 (±50) Å³.

Even more preferably, a=8.135±0.001 Å, b=12.936±0.001 Å, andc=35.435±0.001 Å.

From the single crystal structure it is obvious that form H1 representsa heptasolvate and more specifically a heptahydrate.

The Single Crystal X-Ray Structure is depicted in FIG. 33.

The heptasolvates according to the invention, more preferably theheptahydrates according to the invention and the desolvates thereof, andespecially crystalline form H1 can be characterised, alternatively oradditionally, by Powder X-Ray Diffraction.

Preferably, the heptasolvates according to the invention, morepreferably the heptahydrates according to the invention and thedesolvates thereof, and especially crystalline form H1 can becharacterised, alternatively or additionally, by Powder X-RayDiffraction and more preferably by the Powder X-Ray Diffraction patterncomprising one or more of the Powder X-ray peaks given below, morepreferably comprising 3 or more of the Powder X-ray peaks given below,even more preferably 6 or more of the Powder X-ray peaks given below,and especially comprising all of the of the Powder X-ray peaks givenbelow:

Miller D ± 0.1 °2θ (Cu—Kα₁ indizes No. [Å] radiation) ± 0.1° h k l 117.7 5.0 0 0 2 3 10.4 8.5 0 1 2 5 7.4 12.0 1 0 2 6 7.3 12.1 0 1 4 8 6.813.1 1 1 1 9 6.7 13.2 1 0 3 11 5.9 14.9 1 1 3 12 5.4 16.3 1 1 4 13 5.017.7 1 2 1 15 4.7 19.1 1 2 3 18 4.0 22.4 2 0 2 21 3.4 26.1 0 1 10

More preferably, the heptasolvates according to the invention, morepreferably the heptahydrates according to the invention and thedesolvates thereof, and especially crystalline form H1 can becharacterised, alternatively or additionally, by Powder X-RayDiffraction and more preferably by the Powder X-Ray Diffraction patterncomprising one or more of the Powder X-ray peaks given below, morepreferably comprising 5 or more of the Powder X-ray peaks given below,even more preferably 9 or more of the Powder X-ray peaks given below,and especially comprising all of the of the Powder X-ray peaks givenbelow:

°2θ (Cu—Kα₁ Miller radiation) ± indizes No. D [Å] 0.1° h k l 1 17.7 5.00 0 2 2 12.2 7.3 0 1 1 3 10.4 8.5 0 1 2 4 8.9 10.0 0 0 4 5 7.4 12.0 1 02 6 7.3 12.1 0 1 4 7 6.9 12.8 1 1 0 8 6.8 13.1 1 1 1 9 6.7 13.2 1 0 3 106.4 13.8 1 1 2 11 5.9 14.9 1 1 3 12 5.4 16.3 1 1 4 13 5.0 17.7 1 2 1 154.7 19.1 1 2 3 17 4.1 21.8 1 1 7 18 4.0 22.4 2 0 2 19 3.9 22.8 1 0 8 213.4 26.1 0 1 10 22 3.4 26.2 2 1 5

Even more preferably, the heptasolvates according to the invention, morepreferably the heptahydrates according to the invention and thedesolvates thereof, and especially crystalline form H1 can becharacterised, alternatively or additionally, by Powder X-RayDiffraction and more preferably by the Powder X-Ray Diffraction patterncomprising one or more of the Powder X-ray peaks given below, morepreferably comprising 8 or more of the Powder X-ray peaks given below,even more preferably 10 or more of the Powder X-ray peaks given below,and especially comprising all 12 of the of the Single Crystal X-raypeaks given below:

Miller D ± 0.1 °2θ (Cu—Kα₁ indizes No. [Å] radiation) ± 0.1° h k L 117.7 5.0 0 0 2 2 12.2 7.3 0 1 1 3 10.4 8.5 0 1 2 4 8.9 10.0 0 0 4 5 7.412.0 1 0 2 6 7.3 12.1 0 1 4 7 6.9 12.8 1 1 0 8 6.8 13.1 1 1 1 9 6.7 13.21 0 3 10 6.4 13.8 1 1 2 11 5.9 14.9 1 1 3 12 5.4 16.3 1 1 4 13 5.0 17.71 2 1 14 4.7 18.8 0 1 7 15 4.7 19.1 1 2 3 16 4.1 21.6 1 2 5 17 4.1 21.81 1 7 18 4.0 22.4 2 0 2 19 3.9 22.8 1 0 8 20 3.9 23.0 2 1 1 21 3.4 26.10 1 10 22 3.4 26.2 2 1 5 23 3.4 26.3 2 2 2

The Powder X-Ray Diffraction and more preferably the Powder X-RayDiffraction pattern can preferably be performed or determined asdescribed herein and especially performed or determined by standardtechniques as described in the European Pharmacopeia 6^(th) Editionchapter 2.9.33, and is even more preferably obtained with the parametersCu—Kα₁ radiation and/or λ=1.5406 Å, preferably on a Stoe StadiP 611 KLdiffractometer.

Preferably, the heptasolvates according to the invention, morepreferably the heptahydrates according to the invention and thedesolvates thereof, and especially crystalline form H1, can becharacterised, alternatively or additionally, by theinfrared-spectroscopy data. The IR-spectroscopy data can be preferablyobtained by FT-IR-spectroscopy, The IR-spectroscopy data orFT-IR-spectroscopy data can be preferably obtained by standardtechniques as described in the European Pharmacopeia 6^(th) Editionchapter 2.02.24. For the measurement of the FT-IR-spectra, preferably aBruker Vector 22 spectrometer can be used. FT-IR spectra are preferablybase-line corrected, preferably using Bruker OPUS software.

Preferably, the heptasolvates according to the invention, morepreferably the heptahydrates according to the invention and thedesolvates thereof, and especially crystalline form H1, can becharacterised, alternatively or additionally, by the Raman-spectroscopydata.

The Raman or FT-Raman spectrum is preferably obtained usingAluminium-cups as sample holders for the respective solid material.

The Raman-spectroscopy data is preferably obtained byFT-Raman-spectroscopy, The Raman-spectroscopy data orFT-Raman-spectroscopy data can be preferably obtained by standardtechniques as described in the European Pharmacopeia 6^(th) Editionchapter 2.02.48. For the measurement of the FT-Raman-spectra, preferablya Bruker RFS 100 spectrometer can be used. FT-Raman spectra arepreferably base-line corrected, preferably using Bruker OPUS software.

Preferably, the heptasolvates according to the invention, morepreferably the heptahydrates according to the invention and thedesolvates thereof, and especially crystalline form H1, can becharacterised, alternatively or additionally, by dynamic vapour sorptionexperiments. The results can be obtained by standard techniques asdescribed in Rolf Hilfiker, ‘Polymorphism in the PharmaceuticalIndustry’, Wiley-VCH. Weinheim 2006 (Chapter 9: Water Vapour Sorption,and references therein).

Thus, a preferred subject of the instant invention is a solid materialof a compound according to formula I,

cyclo-(Arg-Gly-Asp-DPhe-NMeVal)  (I)

wherein said solid material comprises one or more crystalline forms ofthe compound of formula I, characterised by a unit cell with the latticeparameters lattice parameters (ULP) ULP3:

a1=8.1±0.5 Å,

b1=12.9±0.7 Å

and

c1=35.4±1.5 Å,

more preferably by a unit cell with the unit cell lattice parameters(ULP) ULP3:

a1=8.1±0.3 Å,

b1=12.9±0.5 Å

and

c1=35.4±1.0 Å,

and especially by a unit cell with the unit cell lattice parameters(ULP) ULP3:

a1=8.1±0.1 Å,

b1=12.9±0.1 Å

and

c1=35.4±0.1 Å.

Said unit cell is preferably a crystallographic unit cell or acrystallographically determined unit cell.

In said unit cell, the angle α preferably is 90°±2°, the angle βpreferably is 90°±2° and/or the angle γ preferably is 90°±2°.

Preferably, the solid material comprises at least 10% by weight, morepreferably at least 30% by weight, even more preferably 60% by weightand especially at least 90% by weight or at least 95% by weight, of oneor more crystalline forms of the compound of formula I as defined aboveand/or below. For example, the solid material comprises about 25, about50, about 75, about 95, about 99 or about 100% by weight of one or morecrystalline forms of the compound of formula I as defined above and/orbelow.

Especially preferably, the solid material comprises at least 10 mole %,more preferably at least 30 mole %, even more preferably 60 mole % andespecially at least 90 mole % or at least 95 mole %, of one or morecrystalline forms of the compound of formula I as defined above and/orbelow. For example, the solid material comprises about 25, about 50,about 75, about 95, about 99 or about 100 mole % of one or morecrystalline forms of the compound of formula I as defined above and/orbelow.

Especially preferred is a solid material as defined above that comprisesthe crystalline form H1 or a desolvate thereof, wherein the crystallineform H1 is characterised by one or more of the parameters given herein,said parameters preferably including the unit cell parameters ULP3 asgiven herein.

Especially preferred is a solid material as defined above thatessentially consists of the crystalline form H1 or a desolvate thereof,wherein the crystalline form H1 is characterised by one or more of theparameters given herein, said parameters preferably including the unitcell parameters ULP3 as given herein.

Another preferred subject of the invention is thus a solid material thatcomprises one or more, preferably one, two, three or four, even morepreferably one or two, crystalline forms of the compound of formula I,each having a unit cell with lattice parameters (ULP) selected from agroup consisting of

ULP1:

a1=9.5±0.5 Å,

b1=26.0±1.5 Å,

and

c1=14.3±0.7 Å,

ULP2:

a2=9.8±0.5 Å,

b2=20.0±1.5 Å,

and

c2=15.4±0.7 Å,

and

ULP3:

a3=8.1±0.5 Å,

b3=35.4±1.5 Å,

and

c3=12.9±0.7 Å.

More preferably, the solid material comprises one or more, preferablyone, two, three or four, even more preferably one or two, crystallineforms of the compound of formula I, each having a unit cell with latticeparameters (ULP) selected from a group consisting of

ULP1:

a1=9.5±0.3 Å,

b1=26.0±1.0 Å,

and

c1=14.3±0.5 Å,

ULP2:

a2=9.8±0.3 Å,

b2=20.0±1.0 Å,

and

c2=15.4±0.5 Å

and

ULP3:

a3=8.1±0.5 Å,

b3=35.4±1.5 Å,

and

c3=12.9±0.7 Å.

In the unit cell with lattice parameters ULP1, ULP2 and/or ULP3, theangle α preferably is 90°±2°, the angle β preferably is 90°±2° and/orthe angle γ preferably is 90°±2°.

Preferably, the unit cell with lattice parameters ULP1, ULP2 and/or ULP3can be characterised, alternatively or additionally, preferablyadditionally, by a content of about 4 molecules of the compound offormula I within said unit cell.

In the unit cell with lattice parameters ULP2 and/or ULP3, the angle αpreferably is 90°±0.5°, the angle β preferably is 90°±0.5° and/or theangle γ preferably is 90°±0.5°. In the unit cell with lattice parametersULP2 and/or ULP3, the angles α, β and γ more preferably are 90°±0.1°.

Preferably, the unit cell with lattice parameters ULP1, ULP2 and/or ULP3can be characterised, alternatively or additionally, preferablyadditionally, by a content of about 4 molecules of the compound offormula I within said unit cell.

Preferably, the unit cell with lattice parameters ULP3 can becharacterised, alternatively or additionally, preferably additionally,by a content of about 4 molecules of the compound of formula I withinsaid unit cell.

More preferably, the solid material comprises one or more, preferablyone, two, three or four, even more preferably one or two, crystallineforms of the compound of formula I, selected from

crystalline form A1, characterised by a unit cell with the latticeparameters a=9.8±0.1 Å, b=19.5±0.5 Å, and c=15.4±0.1 Å,crystalline form S1, characterised by a unit cell with the latticeparameters a=9.4±0.1 Å, b=25.9±0.5 Å, and c=14.1±0.1 Å,crystalline form S2, characterised by a unit cell with the latticeparameters a=9.3±0.1 Å, b=26.6±0.5 Å, and c=14.7±0.1 Å,crystalline form S3, characterised by a unit cell with the latticeparameters a=9.6±0.1 Å, b=25.9±0.5 Å, and c=13.9±0.1 Å, andcrystalline form H1, characterised by a unit cell with the latticeparameters a=8.1±0.3 Å, b=35.4±1.0 Å, and c=12.9±0.5 Å

More preferably, the solid material comprises one or more, preferablyone, two, three or four, even more preferably one or two, crystallineforms of the compound of formula I, selected from

crystalline form A1, characterised by a unit cell with the latticeparameters a=9.8±0.1 Å, b=19.5±0.5 Å, and c=15.4±0.1 Å, preferably withα=β=γ=90°±1° and especially with α=β=γ=90°;crystalline form S1, characterised by a unit cell with the latticeparameters a=9.4±0.1 Å, b=25.9±0.5 Å, and c=14.1±0.1 Å, preferably withα=β=γ=90°±2°, and especially with α=90°±1°, β=91°±1, γ=90°±1° andespecially with α=90°, β=91.2°, γ=90°;crystalline form S2, characterised by a unit cell with the latticeparameters a=9.3±0.1 Å, b=26.6±0.5 Å, and c=14.7±0.1 Å, preferably withα=β=γ=90°±1° and especially with α=β=γ=90°; andcrystalline form S3, characterised by a unit cell with the latticeparameters a=9.6±0.1 Å, b=25.9±0.5 Å, and c=13.9±0.1 Å, preferably withα=β=γ=90°±1° and especially with α=β=γ=90°; andcrystalline form H1, characterized by a unit cell with the latticeparameters a=8.1±0.3 Å, b=35.4±1.0 Å, and c=12.9±0.5 Å, preferably withα=β=γ=90°±1° and especially with α=β=γ=90°

Preferably, the crystalline forms S1, S2 S3 and/or H1 can becharacterised, alternatively or additionally, preferably additionally,by a content of about 4 molecules of the compound of formula I withinsaid unit cells.

The crystalline forms S1, S2, S3 and/or H1 are preferably furthercharacterised as solvates.

More preferably, the crystalline form H1 is further characterised asheptasolvate.

In the context of the present invention, solvates and/or heptasolvatespreferably are crystalline solid adducts containing eitherstoichiometric or non-stoichiometric amounts of a solvent incorporatedwithin the crystal structure, i.e. the solvent molecules preferably forma part of the crystal structure. If the incorporated solvent is water,the solvates are also commonly known as hydrates.

As a result, the solvent in the solvates preferably forms a part of thecrystal structure and thus is in general detectable by X-ray methods andpreferably detectable by X-ray methods as described herein.

Preferably, one or more claims 3 to 8 regarding the solid materials andthe disclosure thereto as described herein for solid materialscomprising one more crystalline forms as described herein other thancrystalline form H1 are preferably also applicable to crystalline formH1 and/or solid materials comprising crystalline form H1. Especiallypreferred solid materials in this regard are subject of the claims 3 to8 in this application, preferably including preferred embodiments givenin the description in this regard.

Preferably, one or more methods of treating and the disclosure theretoas described herein for solid materials comprising one more crystallineforms as described herein other than crystalline form H1 is preferablyalso applicable to crystalline form H1 and/or solid materials comprisingcrystalline form H1. Especially preferred methods of treating in thisregard are subject of the methods of treating claims in thisapplication, preferably including preferred embodiments given in thedescription in this regard.

Preferably, one or more processes and the disclosure thereto asdescribed herein for solid materials comprising one more crystallineforms as described herein other than crystalline form H1 is preferablyalso applicable to crystalline form H1 and/or solid materials comprisingcrystalline form H1. Especially preferred processes in this regard aresubject of the process claims in this application, preferably includingpreferred embodiments given in the description in this regard.

Preferably, one or more uses and the disclosure thereto as describedherein for solid materials comprising one more crystalline forms asdescribed herein other than crystalline form H1 is preferably alsoapplicable to crystalline form H1 and/or solid materials comprisingcrystalline form H1. Especially preferred uses in this regard aresubject of the use claims in this application, preferably includingpreferred embodiments given in the description in this regard.

With regard to the compound according to formula I(cyclo-(Arg-Gly-Asp-DPhe-NMeVal)), the following kinds of writing thename are preferably to be regarded as equivalent:

cyclo-(Arg-Gly-Asp-DPhe-[NMe]Val)=cyclo-(Arg-Gly-Asp-DPhe-[NMe]-Val)=cyclo-(Arg-Gly-Asp-DPhe-NMeVal)=cyclo-(Arg-Gly-Asp-DPhe-NMe-Val)=cyclo(Arg-Gly-Asp-DPhe-NMeVal)=cyclo(Arg-Gly-Asp-DPhe-NMe-Val)=cRGDfNMeV=c(RGDfNMeV).

Preferably, cyclo-(Arg-Gly-Asp-DPhe-NMeVal) is also referred to asCilengitide, which is the INN (International Non-propriety Name) of saidcompound.

Cyclo-(Arg-Gly-Asp-DPhe-NMeVal) is preferably employed herein as apharmaceutically acceptable salt, more preferably the pharmacologicallyacceptable hydrochloride salt, and especially preferably employed as theinner (or internal) salt, which is the compoundcyclo-(Arg-Gly-Asp-DPhe-NMeVal) as such.

If not indicated otherwise, a reference to the compound of formula Ipreferably means a reference to the compoundcyclo-(Arg-Gly-Asp-DPhe-NMe-Val) as such, which is preferably the innersalt of said compound. Accordingly, if not indicated otherwise,cyclo-(Arg-Gly-Asp-DPhe-NMe-Val) is preferably also meant to be theinner salt of cyclo-(Arg-Gly-Asp-DPhe-NMe-Val).

Especially preferred according to the invention are subjects asdescribed herein, wherein the characteristics of two or more preferred,more preferred and/or especially preferred embodiments, aspects and/orsubjects are combined into one embodiment, aspect and/or subject.

The term “about” as used herein with respect to numbers, figures, rangesand/or amounts is preferably meant to mean “circa” and/or“approximately”. The meaning of those terms is well known in the art andpreferably includes a variance, deviation and/or variability of therespective number, figure, range and/or amount of plus/minus 15% andespecially of plus/minus 10%.

The invention is explained in greater detail below by means of examples.The invention can be carried out throughout the range claimed and is notrestricted to the examples given here.

Moreover, the following examples are given in order to assist theskilled artisan to better understand the present invention by way ofexamplification. The examples are not intended to limit the scope ofprotection conferred by the claims. The features, properties andadvantages examplified for the compounds, compositions, methods and/oruses defined in the examples may be assigned to other compounds,compositions, methods and/or uses not specifically described and/ordefined in the examples, but falling under the scope of what is definedin the claims.

Preferably, the features, properties and advantages examplified for thecompounds, compositions, methods and/or uses defined in the examplesand/or claims may be assigned to other compounds, compositions, methodsand/or uses not specifically described and/or defined in the examplesand/or claims, but falling under the scope of what is defined in thespecification and/or the claims.

EXPERIMENTAL Analytic Methods IR-Spectroscopy:

FT-IR spectra are preferably obtained on a Bruker Vector 22 spectrometerat room temperature. Therefore standard techniques as described in theEuropean Pharmacopeia 6th Edition chapter 2.02.24 are preferably used.FT-IR spectra are preferably obtained using a KBr pellet as samplepreparation technique. Therefore approximately 3 mg of the sample aregrinded, mixed with KBr and consequently the mixture is grinded in amortar. A spectral resolution of 2 cm⁻¹ and 32 Scans are chosen foracquisition of the spectra. FT-IR spectra are preferably base-linecorrected using Bruker OPUS software.

Raman-Spectroscopy:

FT-Raman spectra are preferably obtained on a Bruker RFS100 spectrometerequipped with a NdYAG laser (wavelength 1064 nm) at room temperature.Therefore standard techniques as described in the European Pharmacopeia6th Edition chapter 2.02.48 are preferably used. FT-Raman spectra arepreferably obtained using a Aluminium-cups as sample holder. About 5 mgof the samples are stuffed mechanically into the sample holders. Aspectral resolution of 1 cm⁻¹ or 2 cm⁻¹, 500 Scans and a laser power of500 mW are preferably chosen for acquisition of the Raman-spectra.

TG or TGA:

TG measurements are preferably carried out on a Mettler Toledo TG 851.Measurements are preferably realised by standard techniques as describedin the European Pharmacopeia 6th Edition chapter 2.02.34. About 10-20 mgof the respective samples are preferably prepared in Aluminium 100 μLpans without lids. Measurements are preferably carried out in nitrogenatmosphere (50 mL/min) with a heating rate of 5 K/min.

DSC:

DSC measurements are preferably carried out on a Mettler Toledo DSC 821.Measurements are preferably realised by standard techniques as describedin the European Pharmacopeia 6th Edition chapter 2.02.34. About 2-10 mgof the respective samples are preferably prepared in Aluminium 40 μLpans with pierced lids. Measurements are preferably carried out innitrogen atmosphere (50 mL/min) with a heating rate of 5 K/min.

XRD:

Powder X-Ray Diffraction patterns are preferably obtained on a StoeStadiP 611 KL equipped with a linear PSD detector at room temperature,preferably by standard techniques as described in the EuropeanPharmacopeia 6th Edition chapter 2.9.33. Therefore Cu—Ka1 or Co—Ka1radiation with a wavelength of 1.5406 Å respectively 1.7889 Å ispreferably used. About 30 mg of the samples are preferably prepared in acapillary. Scans are preferably carried out from 5° to 72° with a stepsize of 0.02° and an integration time of 150 s.

DVS:

Dynamic Vapor Sorption measurements are preferably obtained on a SMS DVSIntrinsic system. The results are preferably obtained by standardtechniques as described by Rolf Hilfiker “Polymorphism in thePharmaceutical Industry” Wiley-VCH Weinheim 2006 (Chapter 9: WaterVapour Sorption, and references therein.) Approx. 2-10 mg of samples arepreferably weighed into an Aluminium 100 μL pan and placed in the sampleincubator of the DVS instrument with microbalance. A nitrogen overallflow rate of 200 mL/min (combined dry and humid stream) is preferablyused for humidifcation. Water vapor sorption isotherms are preferablyacquired at 25° C. in the range 0% relative humidity to 98% relativehumidity mostly with 10% relative humidity steps. For all relativehumidity steps, an equilibrium condition of dm/dt≦0.0005 wt %/min arepreferably used, with a minimum relative humidity step time of 10minutes and a maximum relative humidity step time of 360 minutes whichis preferably used as a timeout if the dm/dt criteria mentioned above isnot been reached.

Example A) Crystallization of the Inner Salt from the Hydrochloride

1.25 g of cyclo-(Arg-Gly-Asp-DPhe-NMeVal) x HCl are dissolved in 10 mlwater. By use of conc. aqueous ammonia pH is adjusted to ˜6.8. Afterstanding over night at 4 C, crystals appear, which are separated byfiltration, washed with ice-cold water, and dried on air. Mother liquoris concentrated to yield additional crystalline product.

Example B) Crystallization of the Inner Salt from the Trifluoroacetate

1.41 g cyclo-(Arg-Gly-Asp-DPhe-NMeVal) x TFA are dissolved in 10 mlwater. By use of conc. aqueous ammonia pH is adjusted to ˜6.8. Afterstanding over night at ambient temperature, crystals appear, which areseparated by filtration, washed with ice-cold water, and dried on air.Mother liquor is concentrated to yield addition crystalline product.

Example C) Chromatographic Production of the Inner Salt

5.04 g cyclo-(Arg-Gly-Asp-DPhe-NMeVal) x TFA are dissolved in 100 mlwater and pH adjusted to ˜7.0 with 25% NH3 aq. The solution is infusedwith aid of pump A onto a 2-pump gradient system RP-HPLC column(Lichrosorb RP8 (10 um) 50×250 mm). First, column is eluted with water,second, chromatographic purification of compound is by elution with agradient of 15-25% 2-propanol in water at 20 ml/min in 2 hrs. Detectionis at 215/254 nm. Fractions are collected and pooled. During evaporationof 2-propanol from pool crystalline inner saltcyclo-(Arg-Gly-Asp-DPhe-NMeVal) precipitates and is collected byfiltration. Mother liquor is concentrated to yield additionalcrystalline product.

Example D) Production of Crystals of the Inner Salt from a Co-SolventMixture

1 g cyclo-(Arg-Gly-Asp-DPhe-NMeVal) is dissolved in 20 mlwater/2-propanol 8:2 vol at 40° C. After 2 days at RT (25° C.)crystalline compound h as precipitated.

Example E) X-Ray Structure Determination of Inner Salt

A crystal from crystalline form S3 is selected for X-ray analysis.Correct covalent structure of the peptide and conformation of thecompound in crystalline solid state shows a tetrahydrate is present with4 molecules according to formula I per unit cell.

mol formula C₂₇H₄₀N₈O₇ × 4 H₂O mol weight 661.25 g/mol crystal size(0.65 × 0.45 × 0.08)mm³ temperature 298 K diffractometer Nonius - CAD4rays Mo Kα wavelength 0.71093 Å monochrome graphit crystal orthorhombicspacegroup P 2₁ 2₁ 2₁ lattice a  9.460(2) Å b 13.853(3) Å c 25.910(6) Åα = β = γ = 90° number of molecules of the compound of 4 formula I perunit cell

Example F) X-Ray Structure Determination of the Anhydrate

A crystal from crystalline form A1 is selected for X-ray analysis.Correct covalent structure of the peptide and conformation of thecompound in crystalline solid state shows an anhydrate is present with 4molecules according to formula I per unit cell.

mol formula C₂₇H₄₀N₈O₇ mol weight 588.67 g/mol crystal size (0.30 × 0.24× 0.24)mm³ temperature 298 K diffractometer XCalibur - Oxford Diffrationrays Mo Kα wavelength 0.71093 Å monochrome graphit crystal orthorhombicspacegroup P 2₁ 2₁ 2₁ lattice a  9.7944(5) Å b 15.3877(7) Å c 19.5090(2)Å α = β = γ = 90° number of molecules of the compound of 4 formula I perunit cell

Example G) X-Ray Structure Determination of the Dihydrate-Monoethanolate

A crystal from crystalline representing one specific example of form S2is selected for X-ray analysis. Correct covalent structure of thepeptide and conformation of the compound in crystalline solid stateshows a dihydrate-monoethanolate is present with 4 molecules accordingto formula I per unit cell.

mol formula C₂₇H₄₀N₈O₇ × C₂H₅OH × 2H₂O mol weight 669.75 g/mol crystalsize (0.24 × 0.16 × 0.04)mm³ temperature 298 K diffractometer XCalibur -Oxford Diffration rays Mo Kα wavelength 0.71093 Å monochrome graphitcrystal orthorhombic spacegroup P 2₁ 2₁ 2₁ lattice a  9.3212(4) Å b13.7377(7) Å c 26.337(2) Å α = β = γ = 90° number of molecules of thecompound 4 of formula I per unit cell

Example H) Manufacture of Crystalline Form H1

Crystalline form H1 is obtained according to the following procedure:Crystalline form S2 is dissolved in 0.9% saline until a clear solutionwith a concentration of 15 mg/mL of the compound of formula I isobtained. The solution is stored at +5° C. under continuous shaking for4 to 9 weeks, whereby small rodlike-shaped crystals precipitate. Singlecrystal X-ray diffraction of the thus obtained crystals prove to becrystalline form H1.

Example I) X-Ray Structure Determination of Crystalline Form H1

A crystal from crystalline form H1 is selected for X-ray analysis.Correct covalent structure of the peptide and conformation of theproduct in crystalline solid state shows a heptahydrate has formed with4 cyclopeptides per crystal unit.

mol formula C₂₇H₄₀N₈O₇ × 7H₂O mol weight 714.81 crystal size (0.50 ×0.24 × 0.20)mm³ temp 298 K diffractometer XCalibur - Oxford Diffrationrays Mo Ka length 0.71093 Å monochrome graphit crystal orthorhombicgroup P 2₁ 2₁ 2₁ lattice a  8.1349(3) Å b 12.9357(4) Å c 35.435(10) Å α= β = γ = 90° mols of the compound of formula 4 I per unit cell

1. Procedure to Obtain Pseudopolymorphic Forms by Stirring inMethanol/Water and Ethanol/Water Mixtures

a) Crystalline tetrasolvates according to the invention and especiallycrystalline forms S1 and S2, can be obtained by slurry conversion fromform A1 in a Methanol/Water mixture (70 v %:30 v %) at 25° C. for 2 daysstirring time and Ethanol/Water mixture (60 v %:40 v %) at 25° C. for 18days stirring time, respectively. General procedure:

Approx. 500 mg of form A1 of Cilengitide are dispersed in 5 ml solventat room temperature. The dispersion is stirred for the mentioned time bya magnetic stirrer and finally filtered.

b) Additionally, crystalline tetrasolvates according invention andespecially crystalline forms S1 and S2 can be manufactured bycompetitive slurry conversion experiments with a mixture of apseudopolymorphic form (for example S1, S2, S3 or mixtures of these)with form A1 (1:1) in Water/Methanol and Water/Ethanol mixtures withdifferent alcohol contents at different temperatures, respectively.

General Procedure:

Approx. 20 mg of a pseudopolymorphic form (for example S1, S2, S3 ormixtures of these) and 20 mg of form A1 of Cilengitide are dispersed in300 μl Water/alcohol mixture at 0° C. or room temperature (25° C.). Thedispersion is stirred for 24 h and additionally for 3 weeks at RT (25°C.) (long-term experiment) by a magnetic stirrer and finally filtered

In the following table the conditions for the experiments leading to therespective tetrasolvate according to the invention are listed:

i) S1: solvent in the mixture 0° C. for 1 RT for 3 with Water day RT for1 day weeks Methanol 40-100 v % 60-100 v % 60-100 v % Water ad. 100 v %ad. 100 v % ad. 100 v %

ii) S2: solvent in the mixture 0° C. for 1 RT for 3 with Water day RTfor 1 day weeks Ethanol  20-80 v %  40-80 v %  40-70 v % Water ad. 100 v% ad. 100 v % ad. 100 v %

c) In contrast thereto, under the following conditions, none of thepseudopolymorphic forms could be obtained, but essentially pureanhydrate/ansolvate A1 is formed instead.

Approx. 20 mg of a pseudopolymorphic form (for example S1, S2, S3 ormixtures of these) and 20 mg of form A1 of Cilengitide are dispersed in300 μl Water/alcohol mixture at 50° C. The dispersion is stirred for 24h by a magnetic stirrer and finally filtered.

In the following table the conditions for the experiments leading toform A1 are listed.

solvent in solvent in the mixture 50° C. for 1 the mixture 50° C. for 1with Water day with Water day Methanol 90-100 v % Ethanol 90-100 v %Water ad. 100 v % Water ad. 100 v %

Water “ad. 100 v %” preferably means that water is added to the beforespecified amount of solvent other than water (in volume percent (v %))in an amount to make up for 100 v % of the respective solvent/watermixture.

2. Procedure to Obtain Form S1 by Conditioning Experiments UnderMethanol Atmosphere in an Desiccator

Approx. 1 g of a pseudopolymorphic form (for example S2, S3 or mixturesof these) are dried in an dessicator above silica gel. Then the materialis stored in an desiccator with 100% Methanol vapour atmosphere for 5days.

3. Procedure to Obtain Form S2 by Conditioning Experiments Under EthanolAtmosphere in an Desiccator

Approx. 1 g of a pseudopolymorphic form (for example S3, S1, or mixturesof these) are dried in an dessicator above silica gel. Then the materialis stored in an desiccator with 100% Ethanol vapour atmosphere for 5days.

4. Procedure to Convert A1/S3 Polymorphic Mixtures to S2 by Stirring inEthano/Water Mixtures

Cilengitide (mixture of polymorph A1 and S3, 275.5 g) is suspended in amixture of deionized water (700 ml) and ethanol (700 ml). The suspensionis stirred at room temperature for 24 h and then cooled to 5° C. Theproduct is isolated by sucction filtration and washed with cold ethanol.Drying under vacuum for 72 h at 60° C. yields 270 g of Cilengiti de(crystal form S2), 3.6% EtOH, HPLC purity: 99.9%).

5. Manufacture of Crystalline Form A1 by Slurry Conversion

Form A1 of Cilengitide can be obtained by slurry conversion frompseudopolymorphic forms (for example S1, S2, S3 or mixtures of these) inWater at 25° C. An increased temperature (50° C.) accelerates theconversion to form A1.

Approx. 10 g of a pseudopolymorphic form (for example S1, S2, S3 ormixtures of these) of Cilengitide are dispersed in 50 ml deionised waterat room temperature. The dispersion is stirred for 24 h by a magneticstirrer and finally filtered.

6. Manufacture of Crystalline Form A1 by Competitive Slurry Conversion

Also the pure form A1 can be manufactured by competitive slurryconversion experiments with a mixture of a pseudopolymorphic form (forexample S1, S2, S3 or mixtures of these) and A1 (1:1) in Acetone,Acetonitrile, Isopropanol, physiological NaCl solution, Phosphate buffer(pH 7.4) and 1:1 (v:v) mixtures of Acetone, Acetonitrile, Isopropanolwith Water at RT (25° C.).

Approx. 20 mg of a pseudopolymorphic form (for example S1, S2, S3 ormixtures of these) and 20 mg of form A1 of Cilengitide are dispersed in200-700 μl solvent at room temperature. The dispersion is stirred for 5days and additionally 26 days (long-term experiment) at RT (25° C.) by amagnetic stirrer and finally filtered.

7. Competitive Slurry Conversion

Additionally form A1 can be manufactured by competitive slurryconversion experiments with a mixture of a pseudopolymorphic form (forexample S1, S2, S3 or mixtures of these) and form A1 (1:1) inWater/Methanol and Water/Ethanol mixtures with different alcoholcontents at different temperatures. In the following table theconditions for the experiments leading to the pure form A1 are listed.

solvent in the mixture 0° C. for 1 RT for 3 50° C. for 1 with Water dayRT for 1 day weeks day Methanol 0 v % 0-50 v % 0-40 v % 0-70 v % water100 v % ad. 100 v % ad. 100 v % ad. 100 v % Ethanol 0-10 v % 0-30 v %0-20 v % 0-80 v % water ad. 100 v % ad. 100 v % ad. 100 v % ad. 100 v %

Approx. 20 mg of a pseudopolymorphic form (for example S1, S2, S3 ormixtures of these) and 20 mg of form A1 of Cilengitide are dispersed in300 μl Water/alcohol mixture at 0° C., room temperature and 50° C. Thedispersion is stirred for 24 h and additionally for 3 weeks at RT (25°C.) (long-term experiment) by a magnetic stirrer and finally filtered.

8. Procedure to Obtain Crystalline Form S2 Including Crystallizationfrom Ethanol/Water Mixtures

Cyclo-(Arg-Gly-Asp-DPhe-NMeVal)×TFA×H₂SO₄ (400 g) is dissolved in water(1600 ml) at 59° C. The pH is adjusted to pH=6.8 by addition of aqueousammonia (30%). Methanol (9600 ml) is added to the solution over a periodof 3 h. The obtained mixture is cooled to 23° C. within 3 h and stirredat this temperature over night. Then, the mixture is cooled to 5° C. andstirred another 2 h. The precipitated raw product is isolated bysucction filtration and washed with cold methanol. Drying under vacuumfor 48 h at 50° C. yields 335 g of Cilengitide (crystalline form S2,HPLC: 99.8%).

The raw material (335 g) is dissolved in water (1507 g) at 58° C.Methanol (8040 ml) is added to the solution over a period of 3 h. Thethus formed suspension is then cooled to 23° C. within 3 h and stirredat this temperature over night. The suspension is then cooled to 5° C.and stirred for another 3 h. The product is isolated by succtionfiltration and washed with methanol. Drying under vaccuum for 48 h at60° C. yields 309 g of Cilengitide (crystalline form S1, HPLC: 99.9%,3.8% MeOH, IC: <0.1% Cl⁻, 0.0007% TFA and 10.3% SO₄ ²⁻).

The 150 g of the above obtained material are dissolved in water (600 ml)and ethanol (600 ml) at 56° C. The mixture is cooled to 23° C. within 3h and stirred over night. The mixture (suspension) is cooled to 5° C.and stirred for 2 h at this temperature. The product is isolated bysucction filtration and washed with cold water. Drying under vaccuum for48 h at 60° C. yields 115.4 g of Cilengitide (crystalline form S2,≦0.05% Methanol, 5.3% EtOH IC: <0.01% Cl⁻, <0.0011% TFA, 0.34% SO₄ ²⁻).

9. Manufacture of Crystalline Form A1 by Crystallization from Water

A preferred and very efficient method to obtain A1 is by crystallizationfrom water starting from the raw material of Cilengitide as it evolvesfrom the manufacturing processes:

Raw Cilengitide (300 g, either amorphous material, form S1 (?), form S2,form S3 or mixtures thereof) are dissolved in deionized water (1200 ml)at 58° C. The solution is cooled to 23° C. within 3 h and stirred atthis temperature over night. The suspension is then cooled to 5° C. andstirred for 2 h at this temperature. The product is isolated by succtionfiltration and washed with cold deionized water. Drying under vaccuumfor 48 h at 50° C. yields about 230 g of Cilengitide (crystal form A1,<0.001% TFA, 0.22% SO₄ ²⁻, 0.06% Ammonium, 99% HPLC purity, 0.027%water).

10. Dynamic Vapour Sorption Experiments of Crystalline Form S3

A SMS DVS I system is used for the dynamic vapour experiments regardingcrystalline form S3. The results have been obtained by standardtechniques as described in Rolf Hilfiker, ‘Polymorphism in thePharmaceutical Industry’, Wiley-VCH. Weinheim 2006 (Chapter 9: WaterVapour Sorption, and references therein). Water Vapour Sorptionbehaviour shows a loss of water molecules (ca. 9 wt %) within theinitial drying step (0% rh). During the water adsorption cycle there isshown an assembly of water molecules (ca. 10 wt %) in the lattice atelevated rh. In the second desorption cycle there is a loss of thisamount of water. Water Vapor Sorption isotherm (25° C.) of form S3 isdisplayed in FIG. 29.

11. Dynamic Vapour Sorption Experiments of Crystalline Form S1

A SMS DVS Intrinsic is used for the dynamic vapour experiments. Theresults are obtained by standard techniques as described in RolfHilfiker, ‘Polymorphism in the Pharmaceutical Industry’, Wiley-VCH.Weinheim 2006 (Chapter 9: Water Vapour Sorption, and referencestherein). Water Vapour Sorption behaviour shows a mass loss of approx. 8wt % in the first desorption cycle, which is slightly lower than theobserved Methanol mass gain in the Methanol Vapour Sorption experiment.Upon water vapour adsorption, an assembly of water molecules in thelattice is observed, with a maximum weight gain of approx. 8 wt % atelevated rh. In the second desorption cycle a total mass loss of approx.9.9 wt % is observed. For a Cilengitide Dihydrate Di-Methanolate, thecalculated Methanol content equals 9.3 wt %. Water Vapor Sorptionisotherm (25° C.) of form S1 is displayed in FIG. 13.

12. Dynamic Vapour Sorption Experiments of Crystalline Form S2

A SMS DVS Intrinsic is used for the dynamic vapour experiments. Theresults are obtained by standard techniques as described in RolfHilfiker, ‘Polymorphism in the Pharmaceutical Industry’, Wiley-VCH.Weinheim 2006 (Chapter 9: Water Vapour Sorption, and referencestherein). Water Vapour Sorption behaviour shows a mass loss of approx.6.5 wt % in the first desorption cycle, which is lower than the observedEthanol mass gain in the Ethanol Vapour Sorption experiment. Upon watervapour adsorption, an assembly of water molecules in the lattice isobserved, with a maximum weight gain of approx. 6.4 wt % at elevated rh.In the second desorption cycle a total mass loss of approx. 9.2 wt % isobserved. For a Cilengitide Dihydrate Di-Ethanolate, the calculatedEthanol content equals 12.5 wt %. Water Vapor Sorption isotherm (25° C.)of form S2 is displayed in FIG. 20.

13. Conditioning Experiments

a)

Conditioning of amorphous Cilengitide (abbreviated: Cil;Cilengitide=Cyclo-(Arg-Gly-Asp-DPhe-NMeVal)) under mixed water-ethanolatmospheres—representing different water and alcohol partial pressures(adjusted with different EtOH contents (volume %, v %) in the liquidphase) yielded solvates exhibiting different stoichiometries with up to4 molecules of water and up to 2 molecules of ethanol per molecule ofCilengitide. Stoichiometries as determined by Karl-Fischer titration(KF) for quantification of water and head space gas-chromatography(HS-GC) (and nuclear magnetic resonance spectroscopy (NMR)) forquantification of ethanol are depicted in Table 3. In the table alsopoints representing stochiometries with more than 4 molecules of waterper molecule of Cilengitide are visible. As there is no space for morethan 4 molecules of water in the crystal lattice excess amounts of morethan 4 molecules of water represent adsorbed moisture.

Also the modifications and the lattice parameters from indexing of thediffractograms are compiled in Table 3.

TABLE 3 EtOH EtOH EtOH liquid H₂O HS- Σ H₂O HS- EtOH lattice parametersphase KF GC TG Cil KF GC NMR PXRD a b c V [v %] [wt %] [wt %] [wt %][mol] Form [Å] [Å] [Å] [Å³] 0 13.1 — 11.7 1 4.9 0.0 — S3 1 14.1 0.5 13.21 5.4 0.1 — S3 9.5 26.0 13.9 3416 2.5 12.5 1.2 13.3 1 4.7 0.2 0.2 S3 9.526.1 13.9 3431 5 11.3 2.0 12.7 1 4.2 0.3 — S3 9.5 26.1 13.9 3436 10 9.53.2 12.5 1 3.6 0.5 0.5 S2 9.4 26.2 13.9 3438 20 8.4 4.3 13.0 1 3.1 0.60.7 S2 9.5 26.3 13.9 3456 50 7.8 6.9 13.7 1 3.0 1.0 1.0 S2 9.4 26.4 13.93470 50 6.8 6.2 12.6 1 2.5 0.9 — S2 9.5 26.5 14.0 3512 70 6.2 6.4 12.4 12.3 0.9 — S2 9.4 26.4 13.9 3479 80 5.9 6.7 12.8 1 2.2 1.0 — S2 9.5 26.513.9 3492 85 4.1 9.1 12.9 1 1.5 1.3 — S2 90 1.7 12.5 13.8 1 0.6 1.9 — S29.3 26.6 14.7 3636 90 1.2 12.5 13.6 1 0.5 1.9 — S2 95 0.4 13.1 13.7 10.2 1.9 — S2 100 0.7 13.6 14.0 1 0.3 2.0 2.0 S2 9.3 26.6 14.7 3648

In the Table 3 it is shown that there is a floating transition from thehydrate form S3 into the mixed water-ethanol or waterless ethanolsolvate form S2 with increasing ethanol vapour pressure. According tothe X-ray-data obtained from the respective solvates, all solvates(including the hydrates) have similar lattice parameters, which onlyslightly and continuously increase with the assembly of ethanolmolecules.

b)

Conditioning of amorphous Cilengitide (abbreviated: Cil;Cilengitide=Cyclo-(Arg-Gly-Asp-DPhe-NMeVal) under methanol atmosphereyielded a solvate with 2 molecules methanol per molecule Cilengitide.

MeOH MeOH EtOH liquid H₂O HS- Σ H₂O HS- lattice parameters phase KF GCTG Cil KF GC PXRD a b c V [v %] [wt %] [wt %] [wt %] [mol] Form [Å] [Å][Å] [Å³] 100 0.3 10.0 10.4 1 0.1 2.1 S1 9.5 25.9 13.9 3407

1. A solid material of a compound according to formula I,cyclo-(Arg-Gly-Asp-DPhe-NMeVal)  (I) wherein said solid materialcomprises one or more crystalline forms of the compound of formula I,characterised by a unit cell with the lattice parametersa=9.5±0.5 Å,b=23.0±5.0 Å,andc=14.7±1.0 Å.
 2. Solid material according to claim 1, essentiallyconsisting of one or more crystalline forms of the compound of formulaI, characterised by a unit cell with the lattice parametersa=9.5±0.5 Å,b=23.0±5.0 Å,andc=14.7±1.0 Å.
 3. Solid material according to claim 1, wherein the unitcell is monoclinic or orthorhombic.
 4. Solid material according to claim1, wherein the one or more crystalline forms of the compound of formulaI is selected from anhydrates, ansolvates and solvates.
 5. Solidmaterial according to claim 1, wherein the solvates are selected fromhydrates, methanolates and ethanolates, and/or mixed water-methanolsolvates, mixed water-ethanol solvates, mixed water-methanol-ethanolsolvates; and mixtures thereof.
 6. Solid material according to claim 1for the treatment of disorders.
 7. Solid material according to claim 1for the treatment of disorders, selected from cancerous disorders. 8.Solid material according to claim 7, wherein the cancerous disorders areselected from the group consisting of brain cancer, lung cancer, headand neck cancer, breast cancer and prostate cancer, and metastasesthereof.
 9. A method of treating cancerous disorders in a patient,comprising administering to said patient a solid material according toclaim
 1. 10. A method according to claim 9, wherein the cancerousdisorders are selected from the group consisting of brain cancer, lungcancer, head and neck cancer, breast cancer and prostate cancer, andmetastases thereof.
 11. Use of a solid material according to claim 1 forthe manufacture of a medicament for the treatment of disorders.
 12. Useaccording to claim 11, wherein the disorders are selected from theconsisting of brain cancer, lung cancer, head and neck cancer, breastcancer and prostate cancer, and metastases thereof.
 13. Process for themanufacture of a solid material according to claim 1, comprisingcontacting a compound according to formula I with a solvent or solventmixture, preferably a polar and/or protic solvent or solvent mixture,and isolating the solid material according to claim 1 obtained by saidcontacting from said solvent or solvent mixture.
 14. Process for themanufacture of a solid material according to claim 1, comprising a)contacting cyclo-(Arg-Gly-Asp-DPhe-NMeVal) and/or an acid-addition or abase-addition salt thereof with a polar and/or protic solvent or solventmixture b) precipitating and/or crystallising the internal salt ofcyclo-(Arg-Gly-Asp-DPhe-NMeVal) from a polar and/or protic solvent orsolvent mixture, and c) optionally isolating a solid material accordingto claim
 1. 15. Process according to claim 13, wherein said contactingand/or step a), b) and/or c) is performed at a pH value in the range of5.5 to
 8. 16. Process according to claim 13, wherein said contactingand/or step a), b) and/or c) is performed under about isoelectricconditions.
 17. Process according to claim 13, wherein said contactingand/or step a), b) and/or c) is performed in a temperature range between−50° C. and +200° C.
 18. Process according to claim 13, wherein thesolvent or solvent mixture of said contacting and/or step a), b) and/orc) is selected from the group consisting of water, methanol and ethanol,and mixtures thereof.
 19. Process according to claim 14, wherein thesolvent or solvent mixture of step a), b) and/or c) comprises i) 5 to90% by weight of at least one alcohol, selected from the groupconsisting of methanol and ethanol, and ii) 10 to 95% by weight ofwater.
 20. Process according to claim 14, wherein solvent of step a), b)and/or c) essentially consists of water, methanol and ethanol. 21.Process according to claim 14, wherein steps a), b) and/or c) areperformed at a temperature above +60° C. and wherein the solid materialconsists essentially of the one or more crystalline forms.
 22. A solidmaterial of a compound according to formula I,cyclo-(Arg-Gly-Asp-DPhe-NMeVal)  (I) wherein said form comprises one ormore crystalline forms of the compound of formula I, obtainable by aprocess according to claim 13.